AU2008260867B2 - Quinolone compound and pharmaceutical composition - Google Patents

Quinolone compound and pharmaceutical composition Download PDF

Info

Publication number
AU2008260867B2
AU2008260867B2 AU2008260867A AU2008260867A AU2008260867B2 AU 2008260867 B2 AU2008260867 B2 AU 2008260867B2 AU 2008260867 A AU2008260867 A AU 2008260867A AU 2008260867 A AU2008260867 A AU 2008260867A AU 2008260867 B2 AU2008260867 B2 AU 2008260867B2
Authority
AU
Australia
Prior art keywords
fluoro
group
groups
quinolin
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU2008260867A
Other versions
AU2008260867A1 (en
Inventor
Atsushi Mori
Masami Nakai
Yuji Ochi
Kenji Otsubo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Publication of AU2008260867A1 publication Critical patent/AU2008260867A1/en
Application granted granted Critical
Publication of AU2008260867B2 publication Critical patent/AU2008260867B2/en
Ceased legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril

Description

WO 2008/150029 PCT/JP2008/060804 -1 DESCRIPTION QUINOLONE COMPOUND AND PHARMACEUTICAL COMPOSITION TECHNICAL FIELD The present invention relates to a quinolone compound 5 and a pharmaceutical composition. BACKGROUND ART Parkinson's disease is a chronic, progressive neurodegenerative disease that generally develops after middle age. Initial symptoms include unilateral resting tremor, akinesia 10 and rigidity. The tremors, akinesia, and rigidity are called the three major signs of Parkinson's disease, and each of them are caused by the selective death of dopaminergic neurons projected from the substantia nigra to the striatum. The etiology of the disease is still unknown; however, accumulated evidence suggests 15 that an impaired energy-generating system accompanied by abnormal mitochondrial function of nigrostriatal dopaminergic neurons triggers the neurodegenerative disorder of the disease. The mitochondrial dysfunction has been assumed to subsequently cause oxidative stress and failure of calcium homeostasis, thereby 20 resulting in neurodegeneration (Ann.N.Y.Acad.Sci.991:111 119(2003)). Treatments of Parkinson's disease are roughly classified into medical management (medication) and surgical management (stereotaxic operation). Of these, medication is an 25 established therapy and regarded as a basic treatment. In the medication, a symptomatic therapeutic agent is used to compensate for the nigrostriatal dopaminergic neuronal function denatured by Parkinson's disease. L-dopa exhibits the most remarkable therapeutic effects. It is said that no agent exceeds the 30 effectiveness of L-dopa. Currently, L-dopa is used together with a dopa decarboxylase inhibitor to prevent the metabolism thereof in the periphery, and the desired clinical effects have been obtained. However, one disadvantage of the L-dopa treatment is 35 that after several years of usage, the decrement of the WO 2008/150029 PCT/JP2008/060804 -2 durability and stability of the drug's efficacy results in the recurrence of movement disorders such as dyskinesia and daily fluctuation. Moreover, digestive side effects such as nausea and vomiting brought on by the excess release of dopamine, 5 circulatory organ problems such as orthostatic hypotension, tachycardia and arrhythmia, and neurological manifestations such as hallucinations, delusions and distractions have been a cause for concern. Thus, in order to decrease the L-dopa preparation 10 dosage and thereby reducing the side effects, multidrug therapies, in which dopamine receptor agonists, dopamine metabolism enzyme inhibitors, dopamine releaser, central anticholinergic agents and the like are used in combination, are employed. Such therapeutic advances remarkably improve prognoses; even now, however, there 15 is no fundamental cure for Parkinson's disease and other neurodegenerative diseases. Medication must be taken for the rest of the patient's life, and the aforementioned drawbacks decreased efficacy during long-term administration, side effects, and uncontrollable disease progression - can result from L-dopa 20 monotherapy. In addition, it is difficult to expect dramatic effects, even during the employment of multidrug therapies. DISCLOSURE OF THE INVENTION The present invention aims to provide a novel compound that has a functional improvement effect and suppresses of 25 neurological dysfunction by inhibiting the chronic progression of Parkinson's disease or protecting dopamine neurons from the disease etiology, thereby prolonging the period before first L dopa administration begins. The present inventors carried out extensive research to 30 accomplish the aforementioned object, and as a result, they succeeded in producing a compound represented by the following General Formula (1), which comprises protecting and improving mitochondrial functional activity, and protecting and repairing neuron activity. The present invention has been accomplished 35 based on the above findings.
WO 2008/150029 PCT/JP2008/060804 -3 The present invention provides a quinolone compound , a pharmaceutical composition comprising said compound, a use of said compound, a method for treating or preventing a disorder, and a process for producing said compound, as descrived in Item 1 5 to 11 below. Item 1. A quinolone compound represented by General Formula (1) R4 O R5 R3 R6 N R2 R7 R1 10 or a salt thereof, wherein R 1 represents a hydrogen atom, a lower alkyl group, a cyclo C 3
-
8 alkyl lower alkyl group, or a lower alkoxy lower alkyl group; 15 R 2 represents a hydrogen atom, a lower alkyl group, or a halogen-substituted lower alkyl group;
R
3 represents a phenyl group, a furyl group, a thienyl group, or a pyridyl group, each of the groups optionally being substituted with one or more groups selected from the group 20 consisting of the following (1) to (16) on the aromatic or heterocyclic ring represented by the above R 3 : (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups, 25 (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, WO 2008/150029 PCT/JP2008/060804 -4 (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted with one or more lower 5 alkyl groups, (12) carbamoyl groups optionally substituted with one or more lower alkyl groups, (13) cyclo C 3 .8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, 10 (15) morpholinyl carbonyl groups, and (16) a carboxyl group;
R
4 represents a halogen atom; R- represents a hydrogen atom or a halogen atom;
R
6 represents a hydrogen atom; and 15 R 7 represents any one of groups (1) to (15) below: (1) a hydroxy group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, 20 (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted with one or more members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl groups, and cyclo C 3
.
8 alkyl groups, 25 (8) an amino lower alkoxy group optionally substituted on the amino group with one or more members selected from the group consisting of lower alkyl groups, lower alkanoyl groups, lower alkyl sulfonyl groups, and carbamoyl groups optionally substituted with one or more lower alkyl groups, 30 (9) a cyclo C3.
8 alkyloxy group, (10) a cyclo C 3
-
8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group selected from the group consisting of 35 morpholinyl groups, pyrrolidinyl groups, furyl groups, thienyl WO 2008/150029 PCT/JP2008/060804 -5 groups, and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group, and (15) a pyrrolidinyl carbonyl group. 5 Item 2. A quinolone compound of General Formula (1) or a salt thereof according to item 1, wherein R, represents a hydrogen atom or a lower alkyl group;
R
2 represents a hydrogen atom or a lower alkyl group; 10 R 3 represents a phenyl group or a pyridyl group, each of the groups optionally being substituted with one or two groups selected from the group consisting of the following (1), (2), (6), and (8) on the aromatic or heterocyclic ring represented by the above R 3 : 15 (1) lower alkyl groups, (2) lower alkoxy groups, (6) a hydroxy group, and (8) halogen atoms;
R
4 represents a halogen atom; 20 R 5 represents a hydrogen atom;
R
6 represents a hydrogen atom; and
R
7 represents any one of groups (3), (4), and (7) below: (3) a lower alkoxy group, 25 (4) a halogen-substituted lower alkoxy group, and (7) an amino group optionally substituted with one or two lower alkyl groups Item 3. A quinolone compound of General Formula (1) or a 30 salt thereof according to item 2 selected from the group consisting of: 5-fluoro-3-(4-methoxyphenyl) -2-methyl-8-propoxy-1H-quinolin-4-one, 5-fluoro-3-(4-methoxyphenyl) -1-methyl-8-propoxy-1H-quinolin-4-one, 3-(2,4-dimethoxyphenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one, 35 5-fluoro-8-isopropoxy-3-(4-methoxyphenyl) -1H-quinolin-4-one, WO 2008/150029 PCT/JP2008/060804 -6- 3- (2,4-dichlorophenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one, 8-ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one, 5-fluoro-3- (4-methoxy-2-methylphenyl) -8-propoxy-1H-quinolin-4-one, 5-fluoro-3- (4-methoxyphenyl) -8-propoxy-1H-quinolin-4-one, 5 5-fluoro-3- (2-fluoro-4-methoxyphenyl) -8-propoxy-1H-quinolin-4-one, 5-fluoro-3-(4-hydroxyphenyl)-8-propoxy-1H-quinolin-4-one, 8-cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4 one, 5-fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one, 10 5-fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-1H quinolin-4-one, and 5-fluoro-3-(4-methoxyphenyl)-8-(4,4,4-trifluorobutoxy)-1H quinolin-4-one. 15 Item 4. A pharmaceutical composition comprising a quinolone compound of General Formula (1) or a salt thereof according to item 1 as an active ingredient and a pharmaceutically acceptable carrier. 20 Item 5. A prophylactic and/or therapeutic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrion function, comprising as an active ingredient a quinolone compound of General Formula (1) or a salt thereof 25 according to item 1. Item 6. A prophylactic and/or therapeutic agent according to item 5, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, 30 Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal 35 choreoathetosis, essential tremor, essential myoclonus, Gilles de WO 2008/150029 PCT/JP2008/060804 -7 la Tourette's syndrome, Rett's syndrome, degenerative ballism, dystonia musculorum deformance, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, 5 pallidal atrophy, spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's Ataxia, 10 Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary 15 spastic paraparesis, syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiffman syndrome, Klippel-Feil syndrome, Fazio Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age related macular degeneration, and cerebral apoplexy selected from 20 the group consisting of cerebral infarction and cerebral hemorrhage. Item 7. A prophylactic and/or therapeutic agent according to item 5, wherein the disease induced by neurological 25 dysfunction is selected from the group consisting of spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage, and demyelinating diseases selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal 30 leucoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome. Item 8. A prophylactic and/or therapeutic agent 35 according to item 5, wherein the disease induced by deterioration WO 2008/150029 PCT/JP2008/060804 -8 of mitochondrion function is selected from the group consisting of Pearson's syndrome, diabetes, deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, 5 gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to inherited variants of cytochrome b, multiple symmetrical lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANTl disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, 10 ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic-progressive-external-ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, 15 lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, schizophrenia, major depression disorder, bipolar I disorder, bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, 20 intractable depression/chronic depression, double depression and acute renal failure. Item 9. Use of a quinolone compound of General Formula (1) or a salt thereof according to item 1 as a drug. 25 Item 10. A method for treating or preventing neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrion function, comprising administering a quinolone 30 compound of General Formula (1) or a salt thereof according to item 1 to a human or an animal. Item 11. A process for producing a quinolone compound of General Formula (1) WO 2008/150029 PCT/JP2008/060804 -9 R4 0 R5 R3 Re N R2 (1 R7 R1 or a salt thereof, wherein RI, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each defined above in item 1, comprising reacting a compound 5 represented by General Formula (4) (4) Ry RI wherein R 1 , R 4 , R 5 , R 6 and R 7 are each defined above in item 1, with a compound represented by General Formula (5) 10 Ra (5) wherein R 2 and R 3 are each defined above in item 1, and R 8 represents a lower alkoxy group, thereby giving an intermediate compound represented by General Formula (6) 15 WO 2008/150029 PCT/JP2008/060804 -10 RA (6) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each defined above; and subjecting the resulting compound to a cyclization reaction. 5 Specific examples of groups in General Formula (1) are as follows. Examples of lower alkyl groups include straight or branched C 1 - (preferably C 1
.
4 ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n 10 pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2 trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3 methylpentyl, etc. Examples of C 3
-
8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. 15 Examples of cyclo C 3
.
8 alkyl lower alkyl groups include the lower alkyl groups substituted with one to three (preferably one) cyclo C 3
.
8 alkyl group(s) described above. Examples of lower alkoxy groups include straight or branched C 1
.
6 (preferably C 1
..
4 ) alkoxy groups such as methoxy, 20 ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, etc. Examples of lower alkoxy lower alkyl groups include the lower alkyl groups substituted with one to three (preferably one) 25 lower alkoxy group(s) described above. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine. Examples of halogen-substituted lower alkyl groups WO 2008/150029 PCT/JP2008/060804 -11 include the lower alkyl groups substituted with one to seven halogen atom(s), preferably one to three halogen atom(s). Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 5 bromomethyl, dibromomethyl, dichlorofluoromethyl, 2, 2 difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2 fluoroethyl, 2-chloroethyl, 3,3,3 -trifluoropropyl, heptafluoropropyl, 2,2,3,3, 3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3 10 bromopropyl, 4,4, 4-trifluorobutyl, 4,4,4,3, 3-pentafluorobutyl, 4 chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6 -trifluorohexyl, 6-chlorohexyl, perfluorohexyl, etc. Examples of halogen-substituted lower alkoxy groups 15 include the lower alkoxy groups substituted with one to seven halogen atom(s), preferably one to three halogen atom(s). Examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, 20 dichlorofluoromethoxy, 2,2, 2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy, 3,3, 3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3 bromopropoxy, 4,4,4 -trifluorobutoxy, 4,4,4,3, 3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5 25 trifluoropentoxy, 5-chloropentoxy, 6,6,6-trifluorohexyloxy, 6 chlorohexyloxy, etc. Examples of lower alkylthio groups include alkylthio groups wherein the alkyl moiety is the lower alkyl group mentioned above. 30 Examples of hydroxy lower alkyl groups include the above-mentioned lower alkyl groups substituted with one to three (preferably one) hydroxy group(s). Examples of lower alkanoyl groups include straight or branched C 16 (preferably C 14 ) alkanoyl groups such as formyl, 35 acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert- WO 2008/150029 PCT/JP2008/060804 -12 butylcarbonyl, hexanoyl, etc. Examples of lower alkoxycarbonyl groups include alkoxycarbonyl groups wherein the alkoxy moiety is the lower alkoxy group mentioned above. 5 Examples of amino groups optionally substituted with one or more lower alkyl groups include amino groups optionally substituted with one or two lower alkyl group(s) described above. Examples of carbamoyl groups optionally substituted with one or more lower alkyl groups include carbamoyl groups 10 optionally substituted with one or two lower alkyl group(s) described above. Examples of cyclo C 3
-
8 alkyl lower alkyl groups include the above-mentioned lower alkyl groups substituted with one to three (preferable one) cyclo C 3 -8 alkyl group(s) described above. 15 Examples of hydroxy lower alkoxy groups include the above-mentioned lower alkoxy groups substituted with one to three (preferably one) hydroxy group(s). Examples of lower alkoxy lower alkoxy groups include the above-mentioned lower alkoxy groups substituted with one to 20 three (preferably one) lower alkoxy group(s) described above. Examples of amino groups optionally substituted with one or more members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl groups, and cyclo C 3
.
8 alkyl groups include amino groups optionally substituted with one 25 or two members selected from the group consisting of the above mentioned lower alkyl groups, the above-mentioned lower alkoxy lower alkyl groups, and the above-mentioned cyclo C 3
--
8 alkyl groups. Examples of lower alkyl sulfonyl groups include alkyl 30 sulfonyl groups wherein the alkyl moiety is the lower alkyl group mentioned above. Examples of amino lower alkoxy groups optionally substituted on an amino group with one or more members selected from the group consisting of lower alkyl groups, lower alkanoyl 35 groups, lower alkyl sulfonyl groups, and carbamoyl groups WO 2008/150029 PCT/JP2008/060804 -13 optionally substituted with one or more lower alkyl groups include the lower alkoxy groups substituted with one to three (preferably one) amino groupss. Here, the amino lower alkoxy group is optionally substituted on an amino group with one or two 5 members selected from the group consisting of the above-mentioned lower alkyl groups, the above-mentioned lower alkanoyl groups, the above-mentioned lower alkyl sulfonyl groups, carbamoyl groups optionally substituted with one or more lower alkyl groups mentioned above. 10 Examples of cyclo C 3
-
8 alkyloxy groups include groups in which the cyclo C 3
.
8 alkyl group and an oxygen atom are bonded. Examples of tetrahydrofuryl lower alkoxy groups include the above-mentioned lower alkoxy groups substituted with one to three (preferably one) tetrahydrofuryl group(s). 15 Examples of lower alkylthio groups include alkylthio groups wherein the alkyl moiety is the lower alkyl group mentioned above. Examples of phenyl lower alkoxy groups include the above-mentioned lower alkoxy groups substituted with one to three 20 (preferably one) phenyl group(s). Examples of phenyl lower alkoxy lower alkoxy groups include the above-mentioned lower alkoxy groups substituted with one to three phenyl lower alkoxy group(s) (preferably one) described above. 25 The process of producing the compound of the invention is described below in detail. The quinolone compound represented by General Formula (1) (hereinafter also referred to as Compound (1)) can be produced by various methods; for example, by a method according 30 to the following Reaction Scheme 1 or 2.
WO 2008/150029 PCT/JP2008/060804 -14 Reaction Scheme 1 R4 O R4 O R5 X1 R5 R3
R
3 -- B(OH) 2 R, N R2 (3) N R6 N R2 R7 R1 R7 R1 (2) (1) wherein RI, R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above, and X, represents a halogen atom. 5 Examples of halogen atoms represented by Xi include fluorine, chlorine, bromine, and iodine. Preferable leaving groups in the reaction include halogen. Among these, iodine is particularly preferable. Compound (1) can be prepared by reacting the compound 10 of General Formula (2) and the compound of General Formula (3) in an inert solvent or without using any solvents, in the presence or absence of a basic compound, in the presence of a palladium catalyst. Examples of inert solvents include water; ether-based 15 solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2 dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene; lower alcohol-based solvents such as methanol, ethanol, and isopropanol; ketone-based solvents 20 such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more. Palladium compounds used in the reaction are not 25 particularly limited, but include, for example, tetravalent palladium catalysts such as sodium hexachloropalladiumate (IV) tetrahydrate and potassium hexachloropalladiumate (IV); divalent palladium catalysts such as palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) WO 2008/150029 PCT/JP2008/060804 -15 acetylacetonato, dichlorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium (II), dichlorobis(triphenylphosphine)palladium (II), dichlorotetraammine palladium (II), dichloro(cycloocta-1,5 5 diene)palladium (II), palladium (II) trifluoroacetate, and 1,1' bis(diphenylphosphino)ferrocene dichloropalladium (II) dichloromethane complex; zerovalent palladium catalysts such as tris(dibenzylideneacetone)2 palladium (0), tris(dibenzylideneacetone)2 palladium (0) chloroform complex, and 10 tetrakis(triphenylphosphine)palladium (0), etc. These palladium compounds are used singly or in combinations of two or more. In the reaction, the amount of the palladium catalyst is not particularly limited, but is typically in the range from 0.000001 to 20 moles in terms of palladium relative to 1 mol of 15 Compound (2). The amount of the palladium catalyst is preferably in the range from 0.0001 to 5 moles in terms of palladium relative to 1 mol of Compound (2). This reaction advantageously proceeds in the presence of a suitable ligand. Examples of ligands of the palladium 20 catalyst include, for example, 2,2'-bis(diphenylphosphino)-1,1' binaphthyl(BINAP), tri-o-tolylphosphine, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-t butylphosphine, and 9,9-dimethyl-4,5 bis(diphenylphosphino)xanthene (XANTPHOS). These ligands are used 25 singly or in combinations of two or more. The proportion of the palladium catalyst and ligand is not particularly limited. The amount of the ligand is about 0.1 to about 100 moles per mole of the palladium catalyst, and preferably about 0.5 to about 15 moles per mole of the palladium 30 catalyst. Various known inorganic and organic bases can be used as basic compounds. Inorganic bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium 35 hydroxide, and lithium hydroxide; alkali metal carbonates such as WO 2008/150029 PCT/JP2008/060804 -16 sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and 5 potassium; phosphates such as sodium phosphate and potassium phosphate; amides such as sodium amide; and alkali metal hydrides such as sodium hydride and potassium hydride. Organic bases include, for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t 10 butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide, and amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 15 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc. Such basic compounds can be used singly or in combinations of two or more. More preferable basic compounds used 20 in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. A basic compound is usually used in an amount of 0.5 to 10 moles per mole of Compound (2), and preferably 0.5 to 6 moles 25 per mole of Compound (2). Compound (3) is usually used in an amount of at least about 1 mole per mole of Compound (2), and preferably about 1 to about 5 moles per mole of Compound (2). The reaction can be conducted under normal pressure, 30 under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure. The reaction proceeds usually at room temperature to 200 0 C, and preferably at room temperature to 150 0 C, and is usually completed in about 1 to about 30 hours. The reaction is also 35 achieved by heating at 100 to 200 0 C for 5 minutes to 1 hour using WO 2008/150029 PCT/JP2008/060804 -17 a microwave reactor. The compound represented by General Formula (3), which is used as a starting material in Reaction Scheme 1 is an easily available known compound. The compound represented by General 5 Formula (2) includes a novel compound, and the compound is produced in accordance with Reaction Scheme 6 shown below. Reaction Scheme 2 HO R 2 R4RO R, RRRR R, R0 (5)0 R, NH R,, N R2
R
7 R1 (4)R,() , (6) R, R R6 N R2 R7 R1 (1) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined 10 above, and R 8 represents a lower alkoxy group. The lower alkoxy group represented by R 8 in General Formula (5) has the same definition as described above. The compounds represented by General Formulae (4) and (5) are reacted in an inert solvent or without using any solvents, 15 in the presence or absence of an acid catalyst, thereby giving an intermediate compound represented by General Formula (6). Then, the resulting compound was cyclized to produce the compound represented by General Formula (1).
WO 2008/150029 PCT/JP2008/060804 -18 Examples of inert solvents include water; ether-based solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2 dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon-based solvents such 5 as benzene, toluene, and xylene; lower alcohol-based solvents such as methanol, ethanol, and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more. 10 Various kinds of known acid catalysts can be used, including toluenesulfonic acid, methanesulfonic acid, xylene sulfonic acid, sulfuric acid, glacial acetic acid, boron trifluoride, acidic ion exchangers, etc. These acid catalysts can be used singly or in combinations of two or more. 15 Among such acids, acidic ion exchangers are preferably used. Examples of acidic ion exchangers include polymeric cation exchangers available from the market such as Lewatit S100, Zeo karb 225, Dowex 50, Amberlite IR120, or Amberlyst 15 and like styrene sulfonic acid polymers; Lewatit PN, Zeo-karb 215 or 315, 20 and like polysulfonic acid condensates; Lewatit CNO, Duolite CS100, and like m-phenolic carboxylic acid resins; or Permutit C, Zeo-karb 226 or Amberlite IRC 50, and like polyacrylates. Of these, Amberlyst 15 is particularly preferred. An oxide catalyst is usually used in an amount of 25 0.0001 to 100 moles per mole of Compound (4), and preferably 0.5 to 6 moles per mole of Compound (4). In Reaction Scheme 2, Compound (5) is usually used in an amount of at least about 1 mole per mole of Compound (4), and preferably.about 1 to about 5 moles per mole of Compound (4). 30 The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure. The reaction proceeds usually at room temperature to 200 0 C, and preferably at room temperature to 150 0 C. During the 35 reaction, azeotropic removal of water is conducted until the WO 2008/150029 PCT/JP2008/060804 -19 reaction water generation is completed. The reaction is usually finished in about 1 to about 30 hours. The process of producing the compound of General Formula (1) via a cyclization reaction of the intermediate 5 compound represented by General Formula (6) can be employed by heating the compound in a solvent such as diphenyl ether, or by heating the compound in the absence of a solvent. The reaction is conducted at 150 to 300 0 C for 5 minutes to 2 hours. The compound represented by General Formula (4), used 10 as a starting material in Reaction Scheme 2 described above is a known compound or can be produced easily using a known compound. The compound represented by General Formula (5) includes a novel compound, and the compound is manufactured in accordance with, for example, the methods shown in Reaction Scheme 4 and Reaction 15 Scheme 5 described above. Reaction Scheme 3 R4 O R4 O RsR, R, R, R --- X2II ReN R2 (7) R, N R2 H I R, R7 Rj (1a) (1b) wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above, and Ri' is a group represented by Ri other than hydrogen, and X 2 20 represents a group that undergoes the same substitution reaction as that of a halogen or a halogen atom. Halogens represented by X 2 in General Formula (la) include the halogen atom described above. Groups that undergo the same substitution reaction as that of the halogen atoms 25 represented by X 2 include lower alkyl sulfonyloxy groups, aryl sulfonyloxy groups, aralkyl sulfonyloxy groups, etc. Examples of lower alkyl sulfonyloxy groups include straight or branched C1- 6 alkyl sulfonyloxy groups, such as methane sulfonyloxy, ethane sulfonyloxy, n-propane sulfonyloxy, WO 2008/150029 PCT/JP2008/060804 -20 isopropane sulfonyloxy, n-butane sulfonyloxy, tert-butane sulfonyloxy, n-pentane sulfonyloxy, and n-hexane sulfonyloxy. Examples of aryl sulfonyloxy groups include naphthyl sulfonyloxy and phenyl sulfonyloxy optionally substituted on a 5 phenyl ring with one to three group(s) selected from the group consisting of straight or branched C 1
.
6 alkyl groups, straight or branched C 1
.
6 alkoxy groups, nitro groups, and halogen atoms as a substituent. Examples of phenyl sulfonyloxy groups optionally substituted with the above substituent(s) include phenyl 10 sulfonyloxy, 4-methylphenyl sulfonyloxy, 2-methylphenyl sulfonyloxy, 4-nitrophenyl sulfonyloxy, 4-methoxyphenyl sulfonyloxy, 2-nitrophenyl sulfonyloxy, 3-chlorophenyl sulfonyloxy, etc. Examples of naphthyl sulfonyloxy groups include a-naphthyl sulfonyloxy, P-naphthyl sulfonyloxy, etc. 15 Examples of aralkyl sulfonyloxy groups include phenyl substituted straight or branched C 1
-
6 alkyl sulfonyloxy groups that may have, on the phenyl ring, one to three substituent(s) selected from the group consisting of straight or branched CI-6 alkyl groups, straight or branched Ci- 6 alkoxy groups, a nitro 20 group and halogen atoms as a substituent, or naphtyl-substituted straight or branched Ci- 6 alkyl sulfonyloxy groups. Examples of alkyl sulfonyloxy groups substituted with the above-mentioned phenyl group(s) include benzyl sulfonyloxy, 2-phenylethyl sulfonyloxy, 4-phenylbutyl sulfonyloxy, 4-methylbenzyl 25 sulfonyloxy, 2-methylbenzyl sulfonyloxy, 4-nitrobenzyl sulfonyloxy, 4-methoxybenzyl sulfonyloxy, 3-chlorobenzyl sulfonyloxy, etc. Examples of alkyl sulfonyloxy groups substituted with the above-mentioned naphthyl group(s) include a naphthylmethyl sulfonyloxy, P-naphthylmethyl sulfonyloxy, etc. 30 The compound represented by General Formula (lb) can be produced by the reaction of the compound represented by General Formula (la) with the compound represented by General Formula (7) in an inert solvent or without using any solvents, in the presence or absence of a basic compound. 35 Examples of inert solvents include water; ether-based WO 2008/150029 PCT/JP2008/060804 -21 solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2 dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene; lower alcohol-based solvents 5 such as methanol, ethanol, and isopropanol; ketone-based solvents such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more. 10 As a basic compound, various known inorganic bases and organic bases can be used. Inorganic bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as 15 sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; alkali metals such as sodium and potassium; amides such as sodium amide; and alkali metal hydrides 20 such as sodium hydride and potassium hydride. Organic bases include, for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide, and amines such as triethylamine, tripropylamine, 25 pyridine, quinoline, piperidine, imidazole, N-ethyl diisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non 5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4 diazabicyclo[2.2.2]octane (DABCO), etc. 30 Such basic compounds can be used singly or in combinations of two or more. More preferable basic compounds used in the reaction include inorganic bases such as sodium hydride and potassium hydride. A basic compound is usually used in an amount of 0.5 to 35 10 moles per mole of Compound (la), and preferably 0.5 to 6 moles WO 2008/150029 PCT/JP2008/060804 -22 per mole of Compound (la). In Reaction Scheme 1, Compound (7) usually used in an amount of at least about 1 mole per mole of Compound (la), and preferably about 1 to about 5 moles per mole of Compound (la). 5 The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure. The reaction proceeds usually at 0*C to 200 0 C, and preferably at room temperature to 150 0 C, and is usually completed 10 in about 1 to about 30 hours. The compound represented by General Formula (7), which is used as a starting material in Reaction Scheme 3 is an easily available known compound. Compound (5) and Compound (2), which are the starting 15 materials of the compound of the invention, include novel compounds, and can be produced by various methods; for example, by methods according to the following Reaction Schemes 4 to 6. Reaction Scheme 4 0 HO R 2
R
2 R R a R , (9 ) R a R , 0 0 (8) (5) 20 wherein R 2 , R 3 , and R 8 are as defined above, and R 9 represents a lower alkoxy group. The lower alkoxy group represented by R 9 in General Formula (9) has the same definition as described above. The compound represented by General Formula (5) can be 25 produced by the reaction of the compound represented by General Formula (8) with the compound represented by General Formula (9) in an inert solvent or without using any solvents, in the presence or absence of a basic compound. Examples of inert solvents include water; ether-based 30 solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2- WO 2008/150029 PCT/JP2008/060804 -23 dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene; lower alcohol-based solvents such as methanol, ethanol, and isopropanol; ketone-based solvents 5 such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more. As a basic compound, various known inorganic bases and 10 organic bases can be used. Inorganic bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and 15 lithium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; amides such as sodium amide; and inorganic bases of alkali metal hydrides such as sodium hydride and potassium 20 hydride. Organic bases include, for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide; and amines such as triethylamine, tripropylamine, 25 pyridine, quinoline, piperidine, imidazole, N ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non 5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4 diazabicyclo[2.2.2]octane (DABCO), etc. 30 Such basic compounds can be used singly or in combinations of two or more. More preferable basic compounds used in the reaction include inorganic bases such as sodium hydride and potassium hydride. A basic compound is usually used in an amount of about 35 1 to about 10 moles per mole of Compound (8), and preferably WO 2008/150029 PCT/JP2008/060804 -24 about 1 to about 6 moles per mole of Compound (8) In Reaction Scheme 4, Compound (9) is usually used in an amount of at least about 1 mole per mole of Compound (8), and preferably about 1 to about 5 moles per mole of Compound (8). 5 The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure. The reaction proceeds usually at room temperature to 200 0 C, and preferably at room temperature to 150 0 C, and is usually 10 completed in about 1 to about 30 hours. The compounds represented by General Formulae (8) and (9), which are used as starting materials in Reaction Scheme 4, are easily available known compounds. Reaction Scheme 5 HO 2 R , R 3
-X
3 ry ~(9')N R3S 0 0 0 (8' ) 15 (5) wherein R 2 , R 3 , and R 8 are as defined above, and X 3 represents a halogen atom. The halogen atom represented by X 3 in General Formula (9') has the same definition as described above. 20 The compound represented by General Formula (5) can be produced by the reaction of the compound represented by General Formula (8') with the compound represented by General Formula (9') in an inert solvent or without using any solvents, in the presence of a basic compound such as cesium carbonate and a 25 copper catalyst such as copper iodide. Examples of inert solvents include polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more.
WO 2008/150029 PCT/JP2008/060804 -25 The reaction may be conducted in the presence of amino acids such as L-proline. The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or 5 under increased pressure. The reaction proceeds usually at room temperature to 200 0 C, and preferably at room temperature to 150 0 C, and is usually completed in about 1 to about 30 hours. The above reaction is specifically shown in Reference 10 Example 58 below. The compounds represented by General Formulae (8') and (9') used as starting materials in Reaction Scheme 5 described above are known compounds, or can be produced easily using known compounds. 15 Reaction Scheme 6 R4 R4 R, R5 + CH(OR1O)3 R NH 0 R6 NH 2 0 (11) R7 0 R7 (10) O (4) (12) 0 0 annulation reaction R4 0 R4 0 R, X 1 a Xla-Xla (14) R, R N R6N H H Ry R, 20 (2a) (13) wherein R 4 , R 5 , R 6 , and R 7 are as defined above, and Xia represents a halogen atom. R 10 represents a lower alkyl group.
WO 2008/150029 PCT/JP2008/060804 -26 The lower alkyl group represented by R 10 and a halogen atom represented by Xia have the same definitions as described above. The compound represented by General Formula (12) can be 5 produced by the condensation reaction of the compounds represented by General Formulae (4), (10), and (11) in an inert solvent or without using any solvents. Examples of inert solvents include water; ether-based solvents such as dioxane, tetrahydrofuran, diethyl ether, 1,2 10 dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; halogenated hydrocarbon-based solvents such as methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride; aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene; lower alcohol-based solvents such 15 as methanol, ethanol, and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. The compound represented by General Formula (11) can be used as a solvent in place of the solvents mentioned above. These inert solvents can 20 be used singly or in combinations of two or more. In Reaction Scheme 6, Compound (10) is usually used in an amount of at least 1 mole per mole of Compound (4), and preferably about 1 to about 5 moles per mole of Compound (4). An excess amount of Compound (11) is used relative to 25 Compound (10). The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure. The reaction proceeds usually at room temperature to 30 200 0 C, and preferably at room temperature to 150 0 C, and is usually completed in about 1 to about 30 hours. The compound represented by General Formula (13) can be produced by an annulation reaction of the compound represented by General Formula (12) in an inert solvent or without using any 35 solvents.
WO 2008/150029 PCT/JP2008/060804 -27 Examples of inert solvents include ether-based solvents such as diphenyl ether. The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or 5 under increased pressure. The reaction proceeds usually at room temperature to 300 0 C, and preferably at 150 to 300 0 C, and is usually completed in about 1 to about 30 hours. The compound represented by General Formula (2a) can be 10 produced by the reaction of the compound represented by General Formula (13) with the compound represented by General Formula (14) in an inert solvent or without using any solvents, in the presence or absence of a basic compound. Examples of inert solvents include water; ether-based 15 solvents such as dioxane, tetrahydrofuran, diethyl ether, 1, 2 dimethoxyethane, diethylene-glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene; lower alcohol-based solvents such as methanol, ethanol, and isopropanol; ketone-based solvents 20 such as acetone and methyl ethyl ketone; polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more. As a basic compound, various known inorganic bases and 25 organic bases can be used. Inorganic bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and 30 lithium carbonate; alkali metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; alkali metals such as sodium and potassium; amides such as sodium amide; and alkali metal hydrides such as sodium hydride and potassium hydride 35 Organic bases include, for example, alkali metal WO 2008/150029 PCT/JP2008/060804 -28 alkoxide-based solvents such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide; and amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N 5 ethyldiisopropylamine, dimethylaminopyridine, tri-methylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non 5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4 diazabicyclo[2.2.2]octane (DABCO), etc. Such basic compounds can be used singly or in 10 combinations of two or more. More preferable basic compounds used in the reaction include alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, etc. A basic compound is usually used in an amount of 0.5 to 15 10 moles per mole of Compound (13), and preferably 0.5 to 6 moles per mole of Compound (13). In Reaction Scheme 6, Compound (14) is usually used in an amount of at least 0.5 moles per mole of Compound (13), and preferably about 0.5 to about 5 moles per mole of Compound (13). 20 The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure. The reaction proceeds usually at room temperature to 200 0 C, and preferably at room temperature to 150 0 C, and is usually 25 completed in about 1 to about 30 hours. The compounds represented by General Formulae (10), (11) and (14), which are used as starting materials in Reaction Scheme 6, are easily available known compounds. The raw material compounds used in each of the reaction 30 schemes described above may include suitable salts, and the objective compounds obtained via each of the reactions may form suitable salts. These preferable salts include the following preferable salts of Compound (1). Suitable salts of Compound (1) are pharmacologically 35 allowable salts, including metal salts such as alkali metal salts WO 2008/150029 PCT/JP2008/060804 -29 (e.g., sodium salts, potassium salts, and the like); alkaline earth metal salts (e.g., calcium salts, magnesium salts, and the like); ammonium salts; salts of inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, 5 sodium carbonate, cesium carbonate, and the like); alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and the like); alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); salts of 10 organic bases such as tri(lower)alkylamine (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, and the like), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N- (lower) alkyl-morpholine (e.g., N methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 15 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4 diazabicyclo[2.2.2]octane (DABCO); inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, 20 lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and glutamate. In addition, compounds in the form in which solvate (for example, hydrate, ethanolate, etc.) was added to the 25 starting materials and objective compound shown in each of the reaction schemes are included in each of the general formulae. Preferable solvates include hydrate. Each of the objective compounds obtained according to the above reaction schemes can be isolated and purified from the 30 reaction mixture by, for example, after cooling the reaction mixture, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a usual purification procedure such as column chromatography, 35 recrystallization, etc.
WO 2008/150029 PCT/JP2008/060804 -30 The compound of Formula (1) according to the present invention naturally includes geometrical isomers, stereoisomers, optical isomers, and like isomers. The following points should be noted regarding the 5 compound of General Formula (1) shown above. When R, of General Formula (1) represents a hydrogen atom, the compound includes a tautomer of the quinolone ring. That is, when R, represents a hydrogen atom (1') in the quinolone compound of General Formula (1), R5 R3 R,:: N R2 10 (1') wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above, the compound of the tautomer can be represented by Formula (1''), R4 OH R, R3 R7 (1") 15 wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above. That is, both of the compounds represented by Formulae (1') and (1'') are in the tautomeric equilibrium state represented by the following balance formula.
WO 2008/150029 PCT/JP2008/060804 -31 R4
R
4 OH Rs R 3 R6 N R2 H RB N R 2 BR7 (1') R (1") wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above. Such tautomerism between a 4-quinolone compound and a 4-hydroxyquinoline compound is technically known, and it is 5 obvious for a person skilled in the art that both of the above described tautomers are balanced and mutually exchangeable. Therefore, Compound (1) naturally includes the tautomers as mentioned above. In the specification, the constitutional formula of a 10 4-quinolone compound is suitably used as a constitutional formula of the objective or starting material including compounds of such tautomers. The compound of General Formula (1) and the salt thereof are used in the form of general pharmaceutical 15 preparations. The preparations are obtained using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrators, surfactants, lubricants, etc. The form of such pharmaceutical preparations can be selected according to the purpose of the therapy. Typical examples include 20 tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like. To form tablets, any of various carriers conventionally known in this field can be used. Examples thereof include lactose, 25 white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium WO 2008/150029 PCT/JP2008/060804 -32 phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminarin powder, sodium hydrogen carbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium lauryl sulfate, stearic acid 5 monoglycerides, starch, lactose and other disintegrators; white sugar, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; quaternary ammonium bases, sodium lauryl sulfate and other absorption promoters; glycerol, starch and other wetting agents; starch, lactose, kaolin, bentonite, 10 colloidal silicic acid and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol and other lubricants; etc. Further, such tablets may be coated with typical coating materials as required, to prepare, for example, sugar coated tablets, gelatin-coated tablets, enteric-coated tablets, 15 film-coated tablets, double- or multi-layered tablets, etc. To form pills, any of various carriers conventionally known in this field can be used. Examples thereof include glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; gum arabic powder, tragacanth 20 powder, gelatin, ethanol and other binders; laminarin, agar and other disintegrators; etc. To form suppositories, any of various carriers conventionally known in this field can be used. Examples thereof include polyethylene glycol, cacao butter, higher alcohols, 25 esters of higher alcohols, gelatin, semi synthetic glycerides, etc. Capsules can be prepared by mixing the active principal compound with the above-mentioned carriers to enclose the former in a hard gelatin capsule, soft gelatin capsule or the like. 30 To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic to blood. Any of the diluents widely used for such forms in this field can be employed to form the injection. Examples of such diluents include water, ethyl alcohol, macrogol, propylene glycol, 35 ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, WO 2008/150029 PCT/JP2008/060804 -33 fatty acid esters of polyoxyethylene sorbitan, etc. In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerol in an amount sufficient to prepare an isotonic solution, and may contain 5 typical solubilizers, buffers, analgesic agents, etc. Further, if necessary, the pharmaceutical preparation may contain coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines. The amount of the compound represented by the General 10 Formula (1) and the salt thereof included in the pharmaceutical preparation of the present invention is not limited, and can be suitably selected from a wide range. The proportion is generally about 0.1 to about 70 wt.%, preferably about 0.1 to about 30 wt.% of the pharmaceutical preparation. 15 The route of administration of the pharmaceutical preparation of the present invention is not particularly limited, and the preparation is administered by a route suitable to the form of the preparation, patient's age, sex and other conditions, and the status of the disease. For example, tablets, pills, 20 solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with typical injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or 25 intraperitoneally, as required. Suppositories are administered intrarectally. The dosage of the pharmaceutical preparation of the invention is suitably selected according to the method of use, patient's age, sex and other conditions, and severity of the 30 disease. The amount of active principal compound is usually about 0.1 to about 10 mg/kg body weight/day. Further, it is desirable that the pharmaceutical preparation in each unit of the administration form contains the active principal compound in an amount of about 1 to about 200 mg. 35 The use of the compound of the present invention in WO 2008/150029 PCT/JP2008/060804 -34 combination with L-dopa preparations, dopamine receptor agonists, dopamine metabolism enzyme inhibitors, dopamine release-rate promoting preparations, central anticholinergic agents, and the like can achieve effects such as dosage reduction, improvement of 5 side effects, increased therapeutic efficacy, etc., which were not attained by known therapies. EFFECT OF THE INVENTION The compound of the present invention has protecting and improving mitochondrial functional activity and protecting 10 and repairing neuron activity, etc., and thus is effective in the treatment and prevention of neurodegenerative diseases, diseases relating to neurodegenerative disorder, and diseases relating to mitochondrial dysfunction. Neurodegenerative diseases include Parkinson's disease, 15 Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal 20 choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism, dystonia musculorum deformance, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, 25 pallidal atrophy, spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's Ataxia, 30 Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary 35 spastic paraparesis, syringomyelia, syringobulbia, Arnold-Chiari WO 2008/150029 PCT/JP2008/060804 -35 malformation, Stiffman syndrome, Klippel-Feil syndrome, Fazio Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age related macular degeneration and cerebral apoplexy (e.g., 5 cerebral infarction, cerebral hemorrhage, etc.). Diseases induced by neurological dysfunction include spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage and demyelinating diseases (e.g., multiple sclerosis, acute disseminated encephalomyelitis, 10 transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc.) Diseases induced by deterioration of mitochondrion function include Pearson's syndrome, diabetes, deafness, 15 malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to inherited variants of 20 cytochrome b, multiple symmetrical lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency, 25 mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic-progressive-external-ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, schizophrenia, major depression disorder, bipolar I disorder, 30 bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression/chronic depression, double depression, acute renal failure. 35 35a As used herein, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps. 5 Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be .0 expected to be ascertained, understood and regarded as relevant by a person skilled in the art.
WO 2008/150029 PCT/JP2008/060804 -36 BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention is described in more detail with reference to Reference Examples, Examples and Pharmacological Test Examples. 5 Reference Example 1 N-Cyclohexyl-4-fluoro-2-nitro-N-methylaniline Potassium carbonate (6.0 g, 43.5 mmol) and N methylcyclohexylamine (4.6 g, 40.6 mmol) were added to a N methylpyrolidone (NMP) solution (20 ml) of 2,5 10 difluoronitrobenzene (5.0 g, 31.4 mmol), and stirred at 100 0 C for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product 15 was concentrated under reduced pressure to thereby obtain 7.0 g of oily yellow N-cyclohexyl-4-fluoro-2-nitro-N-methylaniline (yield: 89%). 'H-NMR (CDCl 3 ) dppm: 1.12-1.80 (10H, m), 2.67 (3H, s), 3.00-3.09 (lH, m), 7.07-7.20 20 (2H, m), 7.42-7.47(1H, m) The compounds of the following Reference Examples 2 to 5 were prepared in the same manner as in the above Reference Example 1, using corresponding starting materials. 25 Reference Example 2 4-Fluoro-N- (2-methoxyethyl) -N-methyl-2-nitroaniline 'H-NMR (CDCl 3 ) dppm: 2.85 (3H, s), 3.25-3.31 (5H, m), 3.52 (2H, t, J=5.6 Hz), 7.16 30 7.20 (2H, m), 7.43-7.47 (1H, m) Reference Example 3 4-Fluoro-N-isobutyl-N-methyl-2-nitroaniline 1 H-NMR (CDCl 3 ) dppm: 35 0.89 (3H, s), 0.91 (3H, s), 1.89-1.98 (1H, m), 2.81(3H, WO 2008/150029 PCT/JP2008/060804 -37 s), 2.92 (2H, d, J=7.5 Hz), 7.15-7.20 (2H, m), 7.42-7.46 (lH, m) Reference Example 4 4-Fluoro-N-isopropyl-N-methyl-2-nitroaniline 5 H-NMR (CDCl 3 ) dppm: 1.16 (3H, s), 1.19 (3H, s), 2.67 (3H, s), 3.50-3.61 (1H, m), 7.15-7.20 (2H, m), 7.43-7.46 (1H, m) Reference Example 5 10 4-Fluoro-N-methyl-2-nitro-N-propylaniline H-NMR (CDCl 3 ) dppm: 0.84 (3H, t, J=7.5 Hz), 1.51-1.66 (2H, m), 2.77 (3H, s), 3.00 (2H, t, J=7.5 Hz), 7.05-7.20 (2H, m), 7.44 (1H, dd, J=2.75 Hz, J= 8.0 Hz) 15 Reference Example 6 4-Fluoro-2-nitro-1-propylsulfanylbenzene Potassium carbonate (5.0 g, 36.2 mmol) and 1 propanethiol (2.7 g, 35.5 mmol) were added to a N 20 methylpyrolidone (NMP) solution (15 ml) of 2,5 difluoronitrobenzene (5.0 g, 31.4 mmol), and the mixture obtained was stirred at 90 0 C for 2 hours. After the reaction mixture was cooled to room temperature, water (50ml) was added, and the reaction product was extracted with ethyl acetate (100ml). The 25 organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 6.7 g of powdery yellow 4-fluoro-2-nitro-1-propylsulfanylbenzene (yield: 99%). 30 'H-NMR (CDCl 3 ) dppm: 1.06 (3H, t, J=7.5 Hz), 1.68-1.83 (2H, m), 2.89 (2H, t, 7.5 Hz), 7.27-7.42 (2H, m), 7.89 (2H, dd, J=2.75 Hz, J=8.5 Hz) Reference Example 7 35 1-tert-Butoxy-4-fluoro-2-nitrobenzene WO 2008/150029 PCT/JP2008/060804 -38 A tetrahydrofuran (THF) solution (20 ml) of potassium tert-butoxide (3.55 g, 31.6 mmol) was cooled in an methanol-ice bath, and 4.2 g of 2,5-difluoronitrobenzene (26.4 mmol) was further added. The mixture was heated to room temperature, 5 stirred for 96 hours, and further stirred at 60 0 C for 1 hour. Water (2 ml) and 2N-hydrochloric acid (2 ml) were added to the reaction mixture while cooling with an ice water bath, and subsequently water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under 10 reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane : ethyl acetate = 19 : 1). The purified product was concentrated under reduced pressure to thereby obtain 4.5 g of oily orange 1-tert-butoxy-4-fluoro-2 nitrobenzene (yield: 80%). 15 1 H-NMR (CDCl 3 ) dppm: 1.38 (9H, s), 7.18-7.20 (2H, m), 7.47 (1H, d, J=7.1 Hz) Reference Example 8 4-Fluoro-2-nitro-1-propoxybenzene 20 A N,N-dimethylformamide (DMF) solution (3 ml) of potassium carbonate (3.48 g, 25.2 mmol) and 1-iodopropane (3.95 g, 23.2 mmol) was added to a DMF solution (7 ml) of 4-fluoro-2 nitrophenol (3.3 g, 21.0 mmol). The mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, 25 and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution twice, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n hexane : ethyl acetate = 9 : 1). The purified product was 30 concentrated under reduced pressure to thereby obtain 4.03 g of oily yellow 4-fluoro-2-nitro-1-propoxybenzene (yield: 96%). H-NMR (CDCl 3 ) dppm: 1.06 (3H, t, J=7.4Hz), 1.78-1.92 (2H, m), 4.04 (2H, t, J=6.4Hz), 7.04 (1H, dd, J=4.3 Hz, J=9.2Hz), 7.21-7.29 (1H, m), 35 7.58 (1H, dd, J=3.1 Hz, J=7.8Hz) WO 2008/150029 PCT/JP2008/060804 -39 The compounds of the following Reference Examples 9 to 16 were prepared in the same manner as the above Reference Examples 7 to 8, using corresponding starting materials. 5 Reference Example 9 4-Fluoro-1-isopropoxy-2-nitrobenzene 'H-NMR (CDCl 3 ) dppm: 1.36 (3H, s), 4.54-4.63 (lH, m), 7.02-7.05 (1H, m), 10 7.18-7.26 (lH, m), 7.49 (1H, dd, J=3.0 Hz, J=7.5 Hz) Reference Example 10 1-Ethoxy-4-fluoro-2-nitrobenzene IH-NMR (CDCl 3 ) dppm: 15 1.44 (3H, t, J=7.0 Hz), 4.08 (2H, q, J=7.0 Hz), 7.02 (1H, dd, J=4.25 Hz, J=9.25 Hz), 7.22-7.30 (1H, m), 7.56 (1H, dd, J=3.25 Hz, J=7.75 Hz) Reference Example 11 20 1-Cyclopropylmethoxy-4-fluoro-2-nitrobenzene 'H-NMR (CDCl 3 ) dppm: 0.36-0.41 (2H, m), 0.61-0.69 (2H, m), 1.22-1.28 (1H, m), 3.95 (2H, d, J=6.8 Hz), 7.04 (1H, dd, J=4.4 Hz, J=9.2 Hz), 7.20 7.27 (1H, m), 7.57 (1H, dd, J=3.1 Hz, J=7.8 Hz) 25 Reference Example 12 4-Fluoro-2-nitro-1-(4,4,4-trifluorobutoxy)benzene 1 H-NMR (CDCl 3 ) dppm: 2.04-2.16 (2H, m), 2.31-2.44 (2H, m), 4.14 (2H, t, 30 J=5.9 Hz), 7.04 (lH, dd, J=4.3 Hz, J=9.2 Hz), 7.24-7.32 (lH, m), 7.61 (lH, dd, J=3.2 Hz, J=7.8 Hz) Reference Example 13 4-Fluoro-1-(2-methoxyethoxy)-2-nitrobenzene 35 1H-NMR (CDCl 3 ) dppm: WO 2008/150029 PCT/JP2008/060804 -40 3.45 (3H, s), 3.78 (2H, t, J=4.8 Hz), 4.24 (2H, t, J=4.8 Hz), 7.12 (1H, dd, J=4.4 Hz, J= 9.2 Hz), 7.23-7.30 (1H, m), 7.59 (1H, dd, J=3.1 Hz, J= 7.8 Hz) 5 Reference Example 14 1-Cyclopentyloxy-4-fluoro-2-nitrobenzene H-NMR (CDCl 3 ) dppm: 1.62-1.66 (2H, m), 1.83-1.94 (6H, m), 4.82-4.86 (1H, m), 7.04 (1H, dd, J=4.4 Hz, J=9.3 Hz), 7.19-7.27 (lH, m), 7.54 (1H, 10 dd, J=3.2 Hz, J=7.8 Hz) Reference Example 15 1-Cyclobutylmethoxy-4-fluoro-2-nitrobenzene IH-NMR (CDCl 3 ) dppm: 15 1.90-2.02 (4H, m), 2.08-2.15 (2H, m), 2.77-2.81 (1H, m), 4.03 (2H, d, J=6.2 Hz), 7.04 (1H, dd, J=4.3 Hz, J=9.2 Hz), 7.21 7.28 (1H, m), 7.58 (1H, dd, J=3.1 Hz, J=7.8 Hz) Reference Example 16 20 2-(4-Fluoro-2-nitrophenoxymethyl)tetrahydrofuran 1 H-NMR (CDCl 3 ) dppm: 1.88-2.12 (4H, m), 3.80-3.94 (2H, m), 4.11 (2H, d, J=4.0 Hz), 4.27-4.32 (1H, m), 7.10 (1H, 'dd, J=4.4 Hz, J=9.3 Hz), 7.22-7.30 (lH, m), 7.59 (lH, dd, J=3.1 Hz, J=7.8 Hz) 25 Reference Example 17 2-[3-(4-Fluoro-2-nitrophenoxy)propyl]isoindole-1,3-dione Potassium carbonate (10.8 g, 78.1 mmol) and N-(3 bromopropyl)phthalimide (12.1 g, 45.1 mmol) were added to a N, N 30 dimethylformamide (DMF) solution (80 ml) of 4-fluoro-2 nitrophenol (6.0 g, 38.2 mmol), and the mixture was stirred at 60*C for 4 hours. After the reaction mixture was cooled to room temperature, water (200 ml) was added, and the reaction mixture was then cooled with ice. The precipitated insoluble matter was 35 collected by filtration. After being washed with water (50 ml x WO 2008/150029 PCT/JP2008/060804 -41 3), the substance remaining in the filter was air-dried, giving 13.2 g of powdery pale yellow 2-[3-(4-fluoro-2 nitrophenoxy)propyl] isoindole-1, 3-dione (yield: 100%). 'H-NMR (CDCl 3 ) dppm: 5 2.18-2.28 (2H, m), 3.93 (2H, t, J=6.5 Hz), 4.15 (2H, t, J=6.0 Hz), 7.04 (1H, dd, J=4.3 Hz, J=9.2 Hz), 7.23-7.28 (1H, m), 7.58 (1H, dd, J=3.1 Hz, J=7.8 Hz), 7.69-7.74 (2H, m), 7.81-7.85 (2H, m) 10 Reference Example 18 3-(4-Fluoro-2-nitrophenoxy)propylamine 6.5 g of 2-[3-(4-fluoro-2-nitrophenoxy)propyllisoindole 1, 3-dione was suspended in ethanol (140 ml), and hydrazine hydrate (3.0 ml) was added to the resulting suspension. The 15 mixture was stirred for 3.5 hours while heating under reflux. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. 13 ml of 5N sodium hydroxide aqueous solution was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with 20 a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 4.03 g of oily red orange 3-(4-fluoro-2-nitrophenoxy)propylamine (yield: 100%). 25 'H-NMR (CDCla) dppm: 1.92-2.02 (2H, m), 2.94 (2H, t, J=6.5 Hz), 4.19 (2H, t, J=5.9 Hz), 7.07 (1H, dd, J=4.3 Hz, J= 9.2 Hz), 7.22-7.30 (1H, m), 7.59 (1H, dd, J=3.1 Hz, J= 7.8 Hz) 30 Reference Example 19 N-[3- (4-Fluoro-2-nitrophenoxy)propyl]acetamide Pyridine (1.5 ml, 18.6 mmol) and acetic anhydride (0.97 g, 10.3 mmol) were added to a dichloromethane solution of 3-(4 fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol), while being 35 cooled with ice, and then dichloromethane (4 ml) was further WO 2008/150029 PCT/JP2008/060804 -42 added. The resulting mixture was stirred at room temperature for 15 hours. 2N-hydrochloric acid (9.5 ml) was added to the reaction mixture, and the mixture was stirred. Water was added to the mixture, and the resulting mixture was extracted with 5 dichloromethane. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane : methanol = 30 : 1 20 : 1). The purified product was concentrated under reduced 10 pressure to thereby obtain 2.13 g of oily yellow N-[3-(4-fluoro 2-nitrophenoxy)propyl]acetamide (yield: 89%). H-NMR (CDCl 3 ) dppm: 2.04 (3H, s), 2.03-2.12 (2H, m), 3.48-3.55 (2H, m), 4.20 (2H, t, J=5.5 Hz), 6.56 (1H, brs), 7.08 (1H, dd, J=4.3 Hz, 15 J=9.3 Hz), 7.26-7.36 (1H, m), 7.70 (1H, dd, J=3.2 Hz, J=7.8 Hz) Reference Example 20 N-[3-(4-Fluoro-2-nitrophenoxy)propylmethanesulfonamide Pyridine (1.5 ml, 18.6 mmol) and methanesulfonyl 20 chloride (0.8 ml, 10.3 mmol) were added, while being cooled with ice, to a dichloromethane solution of 3-(4-fluoro-2 nitrophenoxy)propylamine (2 .0 g, 9.33 mmol), and dichloromethane (4 ml) was further added. The resulting mixture was stirred at room temperature for 24 hours, and methanesulfonyl chloride (0.12 25 ml, 1.5 mmol) was further added thereto, and then the mixture was stirred at room temperature for 15 hours. 2N hydrochloric acid (9.5 ml) was added to the reaction mixture, and the mixture was stirred. Water was added to the mixture, and the resulting mixture was extracted with dichloromethane. After being washed 30 with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane : ethyl acetate = 4 : 1 -- 1 : 1). The purified product was concentrated under reduced pressure to thereby obtain 1.2 g of 35 oily yellow orange N-[3-(4-fluoro-2- WO 2008/150029 PCT/JP2008/060804 -43 nitrophenoxy)propyl]methansulfonamide (yield: 44%). 'H-NMR (CDCl 3 ) dppm: 2.09-2.18 (2H, m), 3.00 (3H, s), 3.39-3.46 (2H, m), 4.23 (2H, t, J=5.6 Hz), 5.00 (1H, brs), 7.09 (1H, dd, J=4.3 Hz, J=9.2 Hz), 5 7.26-7.35 (1H, m), 7.66 (1H, dd, J=3.1 Hz, J=7.8 Hz) Reference Example 21 Phenyl [3-(4-Fluoro-2-nitrophenoxy)propyl]carbamate Triethylamine (2.90 ml, 21.4 mmol) and phenyl 10 chlorocarbonate (2.52 ml, 20.0 irmol) were added to a dioxane solution (43 ml) of 3-(4-fluoro-2-nitrophenoxy)propylamine (4.03 g, 18.8 mmol), while being cooled with ice, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then 15 purified by silica gel column chromatography (dichloromethane : ethyl acetate = 30 : 1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 5.92 g of powdery yellow phenyl [3-(4-fluoro-2 nitrophenoxy)propyl]carbanate (yield: 94%). 20 1 H-NMR (CDCl 3 ) dppm: 2.09-2.18 (2H, m), 3.48-3.56 (2H, m), 4.21 (2H, t, J=5.7 Hz), 5.69 (1H, brs), 7.05-7.20 (4H, m), 7.26-7.37 (3H, m), 7.65 (1H, dd, J=3.1 Hz, J=7.8 Hz) 25 Reference Example 22 3- [3- (4-Fluoro-2-nitrophenoxy)propyll -1, 1-dimethyl urea A 50% dimethylamine aqueous solution (2.5 ml) was added to a DMF solution (25 ml) of phenyl [3-(4-fluoro-2 nitrophenoxy)propyl]carbamate (5.89 g, 17.6 mmol), and the 30 mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution twice, and concentrated under reduced pressure. The residue was then 35 purified by silica gel column chromatography (dichloromethane : WO 2008/150029 PCT/JP2008/060804 -44 ethyl acetate = 19 : 1 - 4 : 1 -) 2 : 1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 4.10 g of oily pale yellow 3-[3-(4-fluoro-2-nitrophenoxy)propyl] 1, 1-dimethyl urea (yield: 82%). 5 'H-NMR (CDCl 3 ) dppm: 2.03-2.12 (2H, m), 2.89 (6H, s), 3.42-3.49 (2H, m), 4.17 (2H, t, J=5.8 Hz), 4.85 (1H, brs), 7.09 (1H, dd, J=4.3 Hz, J=9.3 Hz), 7.24-7.32 (1H, m), 7.61 (1H, dd, J=3.2 Hz, J=7.8 Hz) 10 Reference Example 23 1-[3-(4-Fluoro-2-nitrophenoxy)propyll-1,3,3-trimethylurea Sodium hydride (55% in oil) (396 mg, 9.1 mmol) was added, while being cooled with ice, to a DMF solution (9 ml) of 2.0 g of 3-[3-(4-fluoro-2-nitrophenoxy)propyll-1,1-dimethyl urea (7.0 15 mmol) and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.735 ml, 11.8 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture and extraction with ethyl acetate was performed. After being washed 20 with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane : ethyl acetate = 9 : 1 -* 6 : 1). The purified product was concentrated under reduced pressure to thereby obtain 0.83 g of 25 oily pale yellow 1-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,3,3 trimethylurea (yield: 40%). H-NMR (CDCl 3 ) dppm: 2.04-2.14 (2H, m), 2.76 (6H, s), 2.83 (3H, s), 3.38 (2H, t, J=6.9 Hz), 4.09 (2H, t, J=5.9 Hz), 7.04 (1H, dd, J=4.3 Hz, 30 J=9.3 Hz), 7.22-7.30 (1H, m), 7.60 (1H, dd, J=3.1 Hz, J=7.7 Hz) Reference Example 24 5-Fluoro-2-propoxyaniline 4-Fluoro-2-nitro-1-propoxybenzene (2.0 g, 10.0 mmol) and 35 5% palladium carbon (750 mg) were added to ethanol (30 ml).
WO 2008/150029 PCT/JP2008/060804 -45 Catalytic reduction was conducted at room temperature and atmospheric pressure (normal pressure). The catalyst was removed by celite filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, 5 and dried over anhydrous magnesium sulfate. The resulting dry product was concentrated under reduced pressure to thereby obtain 1.45g of oily red orange 5-fluoro-2-propoxyaniline (yield: 86%). 1 H-NMR (CDCl 3 ) dppm: 1.04 (3H, t, J=7.4 Hz), 1.74-1.88 (2H, m), 3.89 (2H, brs), 3.90 10 (2H, t, J=6.5 Hz), 6.31-6.46 (2H, m), 6.66 (1H, dd, J=5.1 Hz, J= 8.7 Hz) The compounds of the following Reference Examples 25 to 42 were prepared in the same manner as the above Reference 15 Example 24, using corresponding starting materials. Reference Example 25 5-Fluoro-2-isopropoxyaniline 'H-NMR (CDCla) dppm: 20 1.32 (3H, s), 1.35 (3H, s), 3.88 (2H, brs), 4.38 4.48(1H, m), 6.31-6.46 (2H, m), 6.68-6.73 (1H, m) Reference Example 26 2-Ethoxy-5-fluoroaniline 25 'H-NMR (CDCl 3 ) dppm: 1.39 (3H, t, J=7.0 Hz), 3.90 (2H, brs), 3.97 (2H, q, J=7.0 Hz), 6.31-6.46 (2H, m), 6.63-6.68 (1H, m) Reference Example 27 30 5-Fluoro-2-morpholin-4-ylaniline 'H-NMR (CDCl 3 ) dppm: 2.83 (4H, t, J=4.6 Hz), 3.81 (4H, t, J=4.6 Hz), 4.13 (2H, brs), 6.38-6.45 (2H, m), 6.93-6.97 (1H, m) 35 Reference Example 28 WO 2008/150029 PCT/JP2008/060804 -46 5-Fluoro-2-pyrrolidin-1-ylaniline 'H-NMR (CDCl 3 ) dppm: 1.88-1.94 (4H, m), 2.94-3.00 (4H, m), 4.03 (2H, brs), 6.35-6.46 (2H, m), 6.90-6.95 (1H, m) 5 Reference Example 29 2-Cyclopropylmethoxy-5-fluoroaniline 1 H-NMR (CDCl 3 ) dppm: 0.29-0.35 (2H, m), 0.58-0.65 (2H, m), 1.22-1.29 (lH, m), 10 3.77 (2H, d, J=6.9 Hz), 3.94 (2H, brs), 6.29-6.46 (2H, m), 6.64 (1H, dd, J=5.1 Hz, J=8.8 Hz) Reference Example 30 Ni-Cyclohexyl-4-fluoro-Nl-methylbenzene-1, 2-diamine 15 'H-NMR (CDCl 3 ) dppm: 1.11-1.31(4H, m), 1.55-1.82 (6H, m), 2.57-2.68 (4H, m), 4.18 (2H, brs), 6.33-6.44 (2H, m), 6.92-6.98 (1H, m) Reference Example 31 20 4-Fluoro-N-(2-methoxyethyl)-N 1 -methylbenzene-1, 2-diamine 'H-NMR (CDCl 3 ) dppm: 2.70 (3H, s), 2.96 (2H, t, J=5.4 Hz), 3.39 (3H, s), 3.45 (2H, t, J=5.4 Hz), 4.38 (2H, brs), 6.33-6.43 (2H, m), 6.93-6.99 (iH, m) 25 Reference Example 32 4-Fluoro-N 1 -isobutyl-Nl-methylbenzene-1, 2-diamine 'H-NMR (CDCl 3 ) dppm: 0.92 (3H, s), 0.94 (3H, s), 1.62-1.83 (1H, m), 2.54-2.60 (5H, m), 6.30-6.49 (2H, m), 6.82-6.93 (1H, m) 30 Reference Example 33 4-Fluoro-N'-isopropyl-N-methylbenzene-1, 2-diamine 1 H-NMR (CDCl 3 ) dppm: 1.05 (3H, s), 1.07 (3H, s), 2.55 (3H, s), 3.06-3.17 (1H, m), 4.16 35 (2H, brs), 6.34-6.45 (2H, m), 6.91-6.97 (1H, m) WO 2008/150029 PCT/JP2008/060804 -47 Reference Example 34 4-Fluoro-N'-methyl-Nl-propylbenzene-1, 2-diamine 'H-NMR (CDCl 3 ) dppm: 0.86 (3H, t, J=7.4 Hz), 1.41-1.56 (2H, m), 5 2.57 (3H, s), 2.72 (2H, t, J=7.25 Hz), 4.18 (2H, brs), 6.35-6.44 (2H, m), 6.91-6.97 (1H, m) Reference Example 35 N-[3-(2-Amino-4-fluorophenoxy)propyl]acetamide 10 1 H-NMR (CDCl 3 ) dppm: 1.95-2.05 (2H, m), 1.97 (3H, s), 3.42-3.50 (2H, m), 3.92 (2H, brs), 4.02 (2H, t, J=5.9 Hz), 5.83 (1H, brs), 6.32-6.47 (2H, m), 6.68 (1H, dd, J=5.0 Hz, J=8.8 Hz) 15 Reference Example 36 N-[3-(2-Amino-4-fluorophenoxy)propyl methanesulfonamide 'H-NMR (CDCl 3 ) dppm: 2.02-2.11 (2H, m), 2.94 (3H, s), 3.33-3.40 (2H, m), 3.91 (2H, brs), 4.07 (2H, t, J=5.7 Hz), 4.76 (1H, brs), 6.32-6.46 (2H, m), 20 6.68 (1H, dd, J=5.0 Hz, J=8.8Hz) Reference Example 37 5-Fluoro-2- (4,4, 4-trifluorobutoxy)aniline 1 H-NMR (CDCl 3 ) dppm: 25 2.01-2.12 (2H, m), 2.22-2.41 (2H, m), 3.87 (2H, brs), 4.01 (2H, t, J=6.0 Hz), 6.32-6.47 (2H, m), 6.65 (1H, dd, J=5.0 Hz, J=8.8 Hz) Reference Example 38 30 1-[3-(2-Amino-4-fluorophenoxy)propyl]-1,3,3-trimethylurea 1H-NMR (CDCl 3 ) dppm: 1.99-2.10 (2H, m), 2.78 (6H, s), 2.84 (3H, s), 3.37 (2H, t, J=6.9 Hz), 3.94 (2H, brs), 3.97 (2H, t, J=6.1 Hz), 6.30-6.45 (2H, m), 6.65 (1H, dd, J=5.1 Hz, J=8.8 Hz) 35 WO 2008/150029 PCT/JP2008/060804 -48 Reference Example 39 5-Fluoro-2-(2-methoxyethoxy)aniline IH-NMR (CDCl 3 ) dppm: 3.43 (3H, s), 3.70-3.73 (2H, m), 3.99 (2H, brs), 4.07-4.10 (2H, 5 m), 6.30-6.45 (2H, m), 6.72 (1H, dd, J=5.1 Hz, J=8.7 Hz) Reference Example 40 2-Cyclopentyloxy-5-fluoroaniline 'H-NMR (CDCl 3 ) dppm: 10 1.56-1.66 (2H, m), 1.75-1.87 (6H, m), 3.85 (2H, brs), 4.69-4.72 (1H, m), 6.30-6.45 (2H, m), 6.66 (1H, dd, J=5.1 Hz, J=8.8 Hz) Reference Example 41 2-Cyclobutylmethoxy-5-fluoroaniline 15 1 H-NMR (CDCl 3 ) dppm: 1.86-1.96 (4H, m), 2.08-2.16 (2H, m), 2.74-2.80 (1H, m), 3.90 (2H, brs), 3.91 (2H, d, J=6.7 Hz), 6.31-6.45 (2H, m), 6.66 (1H, dd, J=5.1 Hz, J=8.8 Hz) 20 Reference Example 42 2-tert-Butoxy-5-fluoroaniline 1 H-NMR (CDCl 3 ) dppm: 1.37 (9H, s), 3.87 (2H, brs), 6.27-6.45 (2H, m), 6.85 (1H, dd, J=5.6 Hz, J=8.8 Hz) 25 Reference Example 43 5-Fluoro-2-propylsulfanylaniline 4-Fluoro-2-nitro-1-propylsulfanylbenzene (6.7 g, 31.1 mmol) was dissolved in a mixed solvent of ethanol (40 ml) and 30 water (4 ml). Ammonium chloride (17 g, 0.32 mol) was added to the resulting mixture, and zinc powder (20 g, 0.31 mol) were added little by little. The resulting mixture was then stirred at room temperature for 1 hour. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced 35 pressure to thereby obtain 5.8 g of oily brown 5-fluoro-2- WO 2008/150029 PCT/JP2008/060804 -49 propylsulfanylaniline (yield: 93%). 1H-NMR (CDCl 3 ) dppm: 0.96 (3H, t, J=7.3 Hz), 1.49-1.64 (2H, m), 2.62 (2H, t, J=7.4 Hz), 4.51 (2H, brs), 6.35-6.47 (2H, m), 7.32-7.38 (1H, m) 5 Reference Example 44 4,5-Difluoro-2-propoxyaniline A toluene solution (20 ml) of benzophenone imine (2.38 g, 13.1 mmol), tris(dibenzylidene acetone)dipalladium (275 10 mg, 0.3 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (347 mg, 0.6 mmol) and cesium carbonate(5.83 g, 17.9 mmol) were added to a toluene solution (60 ml) of 1-bromo-4,5 difluoro-2-propoxybenzene (3.0 g, 11.9 mmol). The mixture was stirred under a nitrogen atmosphere at 100 0 C for 23 hours. After 15 the reaction mixture was cooled to room temperature, water and a saturated ammonium chloride aqueous solution were added. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved 20 with diethyl ether (60 ml), and concentrated hydrochloric acid (10 ml) was added to the resulting solution, which was then stirred for 2 hours. A 5N sodium hydroxide aqueous solution (24 ml) was added to the reaction mixture to get a pH =11, and concentrated under reduced pressure. The residue was dissolved in 25 dichloromethane and washed with a saturated sodium chloride aqueous solution. The organic layer was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane : ethyl acetate = 9 : 1). The purified product was concentrated under reduced pressure to 30 thereby obtain 850 mg of oily dark brown 4,5-difluoro-2 propoxyaniline (yield: 38%). 1 H-NMR (CDCl 3 ) dppm: 1.04 (3H, t, J=7.4 Hz), 1.75-1.86 (2H, m), 3.71 (2H, brs), 3.88 (2H, t, J=6.5 Hz), 6.51 (1H, dd, J=8.0 Hz, 11.5 Hz), 6.60 (1H, dd, 35 J=7.3 Hz, J=11.8 Hz) WO 2008/150029 PCT/JP2008/060804 -50 Reference Example 45 1-(2-Amino-4-fluorobenzoyl)pyrrolidine A DMF solution (4 ml) of pyrrolidine (1.93 g, 27.1 5 mmol), a DMF solution (4 ml) of triethylamine (3.79 g, 37.5 mmol), 1-hydroxybenzotriazole (HOBt) (3.11 g, 23.0 mmol), and 1-(3 dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSC) (3.91 g, 20.4 mmol) were added to a DMF solution (4 ml) of 4 fluoroanthranilic acid (2.0 g, 12.8 mmol) in that order. The 10 mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica 15 gel column chromatography (dichloromethane : methanol = 30 : 1). The purified product was concentrated under reduced pressure to thereby obtain 1.65 g of oily orange 1-(2-amino-4 fluorobenzoyl)pyrrolidine (yield: 62%). 'H-NMR (CDCl 3 ) dppm: 20 1.75-2.00 (4H, m), 3.40-3.75 (4H, m), 4.85 (2H, brs), 6.33-6.40 (2H, m), 7.14-7.21 (1H, m) Reference Example 46 Ethyl a- (hydroxymethylene) -4-methoxyphenyl acetate 25 Sodium hydride (60% in oil) (467 mg, 11.7 mmol) was added to a benzene solution (10 ml) of ethyl 4-methoxyphenyl acetate (2.0 g, 10.3 mmol), while being cooled with ice. The mixture was stirred at room temperature for 5 minutes. The stirred mixture was cooled with ice again; ethyl formate (1.02 ml, 30 12.6 mmol) was added thereto, and stirred at room temperature for 3 hours. While being cooled with ice, water and ethyl acetate were added to the reaction mixture, and then 2N hydrochloric acid (6 ml) was added to separate the reaction mixture into two layers. The organic layer was concentrated under reduced pressure, and 35 the residue was then purified by silica gel column chromatography WO 2008/150029 PCT/JP2008/060804 -51 (n-hexane : ethyl acetate = 4 : 1). The purified product was concentrated under reduced pressure to thereby obtain 1.97 g of oily slightly reddish-brown ethyl a-(hydroxymethylene)-4 methoxyphenyl acetate (yield: 86%). The resultant compound 5 undergoes nitrogen substitution, and was stored in a freezer. 1 H-NMR (CDCl 3 ) dppm: 1.28 (3H, t, J=7.1 Hz), 3.81 (3H, s), 4.28 (2H, q, J=7.1 Hz), 6.87 (2H, d, J=8.8 Hz), 7.16-7.26 (3H, m), 12.02 (1H, d, J=12.5 Hz) 10 The compounds of the following Reference Examples 47 to 57 were prepared in the same manner as the above Reference Example 46, using corresponding starting materials. 15 Reference Example 47 Ethyl 2,4-dimethoxy-a-(hydroxymethylene)phenyl acetate 1 H-NMR (CDCl 3 ) dppm: 1.21 (3H, t, J=7.1 Hz), 3.76 (3H, s), 3.81 (3H, s), 4.22 (2H, q, J=7.1 Hz), 6.43-6.49 (2H, m), 7.00 (1H, d, J=8.9 Hz), 20 7.12 (1H, d, J=12.6 Hz), 11.89 (1H, d, J=12.6 Hz) Reference Example 48 Ethyl 2,4-dichloro-a-(hydroxymethylene)phenyl acetate 1 H-NMR (CDCl 3 ) dppm: 25 1.15 (3H, t, J=7.2 Hz), 4.22 (2H, q, J=7.2 Hz), 7.11-7.26 (3H, m), 7.40-7.43 (1H, m), 12.00 (1H, d, J=12.2 Hz) Reference Example 49 Ethyl a- (hydroxymethylene) -2-methoxyphenyl acetate 30 'H-NMR (CDCls) dppm: 1.19 (3H, t, J=7.1 Hz), 3.79 (3H, s), 4.21 (2H, q, J=7.1 Hz), 6.86-7.68 (SH, m), 11.91 (1H, d, J=12.3 Hz) Reference Example 50 35 Ethyl a- (hydroxymethylene) -2-isopropoxy-4 -methoxyphenyl acetate WO 2008/150029 PCT/JP2008/060804 -52 'H-NMR (CDCla) dppm: 1.20-1.31 (9H, m), 3.80 (3H, s), 4.17 (2H, q, J=7.1 Hz), 4.43 4.47 (1H, m), 6.42-6.46 (2H, m), 6.90-7.12 (2H, m), 11.85 (1H, d, J=12.6 Hz) 5 Reference Example 51 Ethyl a-(hydroxymethylene)-4-methoxy-2-methylphenyl acetate H-NMR (CDCl 3 ) dppm: 1.20 (3H, t, J=7.2 Hz), 2.19 (3H, s), 3.80 (3H, s), 4.22 (2H, q, 10 J=7.2 Hz), 6.54-6.75 (2H, m), 7.02-7.26 (2H, m), 11.94 (1H, d, J=12.7 Hz) Reference Example 52 Ethyl 2-fluoro-a-(hydroxymethylene)-4-methoxyphenyl acetate 15 1 H-NMR (CDCl 3 ) dppm: 1.22 (3H, t, J=7.1 Hz), 3.80 (3H, s), 4.21 (2H, q, J=7.1 Hz), 6.61-6.69 (2H, m), 7.03-7.26 (2H, m), 12.05 (1H, d, J=12.3 Hz) Reference Example 53 20 Ethyl 4-ethoxy-a-(hydroxymethylene)-2-methoxyphenyl acetate IH-NMR (CDCl 3 ) dppm: 1.19-1.45 (6H, m), 3.75 (3H, s), 4.00.-4.26 (4H, m), 6.42-6.48 (2H, m), 6.97-7.26 (2H, m), 11.86 (1H, d, J=12.3 Hz) 25 Reference Example 54 Ethyl a-(hydroxymethylene)-4-isopropoxy-2-methoxyphenyl acetate IH-NMR (CDCl 3 ) dppm: 1.20-1.31 (9H, m), 3.75 (3H, s), 4.16 (2H, q, J=7.2 Hz), 4.43 4.47 (1H, m), 6.43-6.48 (2H, m), 6.99-7.22 (2H, m), 11.87 (1H, d, 30 J=12.3 Hz) Reference Example 55 Ethyl 4-cyclopropylmethoxy-a-(hydroxymethylene)phenyl acetate 1 H-NMR (CDCl 3 ) dppm: 35 0.35-0.37 (4H, m), 1.24 (3H, t, J=7.1 Hz), 3.81-3.83 (2H, m), WO 2008/150029 PCT/JP2008/060804 -53 4.25 (2H, q, J=7.1 Hz), 6.85-6.91 (2H, m), 7.16-7.27 (3H, m), 12.02 (lH, d, J=12.5 Hz) Reference Example 56 5 Ethyl a-(hydroxymethylene)-4-methylsulfanylphenyl acetate 'H-NMR (CDCl 3 ) dppm: 1.22 (3H, t, J=7.1 Hz), 2.47 (3H, s), 4.09 (2H, q, J=7.1 Hz), 6.85-6.94 (2H, m), 7.16-7.26 (3H, m), 11.99 (1H, d, J=12.3 Hz) 10 Reference Example 57 Ethyl 4-ethoxy-a-(hydroxymethylene)phenyl acetate 1 H-NMR (CDCl 3 ) dppm: 1.23-1.47 (6H, m), 4.00-4.32 (4H, m), 6.85-6.88 (2H, m), 7.15 7.27 (3H, m), 12.00 (lH, d, J=12.5 Hz) 15 Reference Example 58 Ethyl 4-methoxy-a-propionylphenyl acetate L-Proline (980 mg , 8.52 mmol), copper (I) iodide (810 mg , 4.26 mmol), and cesium carbonate (27.7 g, 85.2 mmol) were 20 added to a dimethylsulfoxide (DMSO) solution (40 ml) of ethyl propionyl acetate (3.8 g, 26.3 mmol) and 4-iodoanisole (5.0 g, 21.3 mmol) in that order. The mixture was stirred under a nitrogen atmosphere at 40 to 45 0 C for 27 hours. The reaction mixture was cooled to room temperature, and then water and 25 ammonium chloride aqueous solution were added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution twice, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane : ethyl 30 acetate = 19 : 1 -> 8 : 1). The purified product was concentrated under reduced pressure to thereby obtain 2.97 g of oily yellow ethyl 4-methoxy-a-propionylphenyl acetate (yield: 56%). 1 H-NMR (CDCl 3 ) dppm: 1.01-1.11 (3H, m), 1.18-1.31 (3H, m), 2.52-2.61 (2H, m), 3.80 and 35 3.82 (3H, s), 4.15-4.24 (2H, m), 4.65 (0.6H, s), 6.84-7.28 (4H, WO 2008/150029 PCT/JP2008/060804 -54 m), 13.13 (0.4H, s) The compound of the following Reference Example 59 was prepared in the same manner as the above Reference Example 58, 5 using corresponding starting materials. Reference Example 59 Ethyl a-acetyl-4-methoxyphenyl acetate 1 H-NMR (CDCl 3 ) dppm: 10 1.16-1.29 (3H, m), 1.85 (1.4H, s), 2.17 (1.6H, s), 3.80 and 3.82 (1.4 and 1.6H, s), 4.13-4.25 (2H, m), 4.62 (0.6H, s), 6.85-7.28 (4H, m), 13.09 (0.4H, s) Reference Example 60 15 5- [ (5-Fluoro-2-propoxyphenylamino )methylene] -2, 2-dimethyl [1,3]dioxane-4,6-dione Meldrum's acid (5.29g, 36.7 mmol) was added to methyl orthoformate (31 ml), and the mixture was stirred for 2 hours while heating under reflux. The resulting mixture was cooled to 20 50 0 C, and 5-fluoro-2-propoxyaniline (4.28 g, 25.3 mmol) and methyl orthoformate (3 ml) were added thereto. The resulting mixture was stirred for 6 hours while heating under reflux. The resulting reaction mixture was then cooled to room temperature, and concentrated under reduced pressure. The residue was 25 recrystallized from methanol to thereby obtain 7.61 g of powdery pale brown 5-[(5-fluoro-2-propoxyphenylamino)methylene]-2,2 dimethyl-[1,3]dioxane-4,6-dione (yield: 93%). 1 H-NMR (CDCl 3 ) dppm: 1.12 (3H, t, J=7.4 Hz), 1.75 (6H, s), 1.85-1.98 (2H, m), 4.02 (2H, 30 t, J=6.3 Hz), 6.86-6.91 (2H, m), 7.06-7.10 (lH, m), 8.60 (lH, d, J=14.6 Hz), 11.68 (1H, d, J=14.8 Hz) The compound of the following Reference Example 61 was prepared in the same manner as the above Reference Example 60, 35 using corresponding starting materials.
WO 2008/150029 PCT/JP2008/060804 -55 Reference Example 61 5- [(2-Cyclopropylmethoxy-5-fluorophenylamino )methylene] -2, 2 dimethyl-[1,3]dioxane-4,6-dione 5 1 H-NMR (CDCl 3 ) dppm: 0.39-0.43 (2H, m), 0.65-0.73 (2H, m), 1.31-1.37 (1H, m), 1.75 (6H, s), 3.92 (2H, d, J=6.9 Hz), 6.86-6.91 (2H, m), 7.07-7.11 (1H, m), 8.60 (lH, d, J=14.5 Hz), 11.69 (1H, d, J=14.3 Hz) 10 Reference Example 62 5-Fluoro-8-propoxy-1H-quinolin-4-one 5- [(5 -Fluoro-2-propoxyphenylamino)methylene] -2,2 dimethyl-[1,3]dioxane-4,6-dione (7.6 g, 23.5 mmol) was added to diphenyl ether (15 ml), and the mixture was heated using a mantle 15 heater, and then kept under reflux for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (5 ml) and n-hexane (10 ml) were added. The resulting mixture was stirred and the resultant insoluble matter was collected by filtration. The filtrate was recrystallized from an ethyl 20 acetate-n-hexane mixed solvent to thereby obtain 3.15 g of powdery dark brown 5-fluoro-8-propoxy-1H-quinolin-4-one (yield: 61%). 1 H-NMR (DMSO-d 6 ) dppm: 1.03 (3H, t, J=7.3 Hz), 1.74-1.88 (2H, m), 4.07 (2H, t, J=6.4 Hz), 25 5.97 (1H, d, J=7.4 Hz), 6.87 (1H, dd, J=8.8 Hz, 11.9 Hz), 7.13 (1H, dd, J=4.0 Hz, J=8.8 Hz), 7.70 (1H, t, J=7.2 Hz), 11.07 (1H, brs) The compound of the following Reference Example 63 was 30 prepared in the same manner as the above Reference Example 62, using corresponding starting materials. Reference Example 63 8-Cyclopropylmethoxy-5-fluoro-lH-quinolin-4-one 35 'H-NMR (DMSO-d 6 ) dppm: WO 2008/150029 PCT/JP2008/060804 -56 0.34-0.40 (2H, m), 0.55-0.61 (2H, m), 1.27-1.33 (1H, m), 3.98 (2H, d, J=7.0 Hz), 5.97 (1H, d, J=7.4 Hz), 6.86 (1H, dd, J=8.8 Hz, J=11.9 Hz), 7.13 (1H, dd, J=4.0 Hz, J= 8.8 Hz), 7.71 (1H, t, J=7.4 Hz), 11.10 (lH, brs) 5 Reference Example 64 5-Fluoro-2-methyl-8-propoxy-1H-quinolin-4-one Amberlyst 15 (1.0 g, a product of Sigma Aldrich Corp.) was added to a benzene solution (200 ml) of 5-fluoro-2 10 propoxyaniline (10 g, 59 mmol) and ethyl acetoacetate (7.7 g, 59 mmol). The mixture was stirred while heating under reflux for 6 hours and using a Dean-Stark trap. The reaction mixture was cooled to room temperature, the resin was removed by filtration, and the filtrate was concentrated under reduced pressure. 15 Diphenyl ether (20ml) was added to the residue. The mixture was heated using a mantle heater and stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter obtained by the addition of n-hexane-ethyl acetate (2 : 1) was collected by filtration. The substance 20 remaining on the filter was washed with n-hexane-ethyl acetate (2 : 1), and dried to thereby obtain 6.0 g of powdery pale yellow 5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one (yield: 43%). 1 H-NMR (DMSO-d 6 ) dppm: 0.97 (3H, t, J=7.3 Hz), 1.77-1.87 (2H, m), 2.34 (3H, s), 4.08 (2H, 25 t, J=6.4 Hz), 5.84 (lH, s), 6.79-6.88 (1H, m), 7.10-7.14 (1H, m), 10.58 (1H, brs) Reference Example 65 5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one 30 5-Fluoro-8-propoxy-lH-quinolin-4-one (1.0 g, 4.52 mmol) was suspended in DMF (11 ml), and potassium carbonate (0.7 g, 5.06 mmol) and iodide (1.27 g, 5.00 mmol) were added to the suspension. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a sodium 35 thiosulfate (3.94 g, 25 mmol) aqueous solution (45 ml). The WO 2008/150029 PCT/JP2008/060804 -57 mixture was stirred for 5 minutes. Ethyl acetate was added to the resulting reaction mixture and stirred, thereby collecting insoluble matter by filtration. The filtrate was separated, and the organic layer was washed with a saturated sodium chloride 5 aqueous solution, and then concentrated under reduced pressure. The residue and the collected insoluble matter were combined, and then purified by silica gel column chromatography (dichloromethane : methanol = 50 : 1 -+ 40 : 1). The purified product was concentrated to dryness under reduced pressure to 10 thereby obtain 1.25 g of powdery pale dark brown 5-fluoro-3-iode 8-propoxy-1H-quinolin-4-one (yield: 80%). 1H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.4 Hz), 1.78-1.86 (2H, m), 4.09 (2H, t, J=6.5 Hz), 6.97 (1H, dd, J=8.8 Hz, J= 11.9 Hz), 7.19 (1H, dd, J=4.0 Hz, 15 J=8.8 Hz), 8.19 (1H, s), 11.44 (1H, brs) The compounds of the following Reference Examples 66 and 67 were prepared in the same manner as the above Reference Example 65, using corresponding starting materials. 20 Reference Example 66 5-Fluoro-3-iodo-2-methyl-8-propoxy-1H-quinolin-4-one 1 H-NMR (CDCl 3 ) dppm: 0.97 (3H, t, J=7.4 Hz), 1.78-1.88 (2H, m), 2.70 (3H, s), 6.92 25 7.00 (1H, m), 7.17-7.22 (1H, m) Reference Example 67 8-Cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one 'H-NMR (DMSO-d 6 ) dppm: 30 0.36-0.40 (2H, m), 0.56-0.63 (2H, m), 1.28-1.31 (lH, m), 3.99 (2H, d, J=7.0 Hz), 6.97 (1H, dd, J=8.8 Hz, J=11.9 Hz), 7.19 (1H, dd, J=4.0 Hz, J=8.8 Hz), 8.19 (1H, s), 11.48 (lH, brs) Reference Example 68 35 8-Cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one WO 2008/150029 PCT/JP2008/060804 -58 Potassium carbonate (450 mg, 3.26 mmol) was added to a DMF solution (5 ml) of 8-cyclopropylmethoxy-5-fluoro-3-iodo-1H quinolin-4-one (910 mg, 2.53 mmol). The mixture was stirred for 15 minutes at room temperature. Ethyl iodide (0.31 ml, 3.87 mmol) 5 was added thereto, and the resulting mixture was stirred at 60 0 C for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was then purified by 10 silica gel column chromatography (dichloromethane : ethyl acetate = 40 : 1 -> 15 : 1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 750 mg of powdery pale dark brown 8-cyclopropylmethoxy-1-ethyl-5-fluoro-3 iodo-1H-quinolin-4-one (yield: 77%). 15 'H-NMR (DMSO-d 6 ) dppm: 0.34-0.38 (2H, m), 0.57-0.64 (2H, m), 1.26-1.36 (4H, m), 3.93 (2H, d, J=7.3 Hz), 4.56 (2H, q, J=7.0 Hz), 7.05.(1H, dd, J=8.9 Hz, J= 11.4 Hz), 7.24 (1H, dd, J=4.6 Hz, J= 9.0 Hz), 8.45 (1H, s) 20 Reference Example 69 2,2,2-Trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide A dichloromethane solution (60 ml) of 5-fluoro-2 propoxyaniline (10.0g, 59.1 mmol) was cooled with ice, and triethylamine (16.5 ml) was added thereto. Then, trifluoroacetic 25 anhydride (14.8 g, 70.5 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The resulting dry 30 product was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane ethyl acetate = 10 : 1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 15.83 g of powdery white 2,2,2-trifluoro-N-(5-fluoro-2 35 propoxyphenyl)acetamide (yield: 99%).
WO 2008/150029 PCT/JP2008/060804 -59 1 H-NMR (CDCl 3 ) dppm: 1.03 (3H, t, J=7.5 Hz), 1.79-1.93 (2H, m), 3.98 (2H, t, J=6.5 Hz), 6.80-6.86 (2H, m), 8.10-8.12 (lH,' m), 8.64 (1H, brs) 5 Reference Example 70 Ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino) buta-2-enoic acid Carboethoxymethylene triphenylphosphorane (41.52 g, 119.2 mmol) was added to a toluene solution (100 ml) of 2,2,2 10 trifluoro-N-(5-fluoro-2-propoxyphenyl)acetamide (15.83 g, 59.1 mmol). The mixture was stirred under a nitrogen atmosphere while heating under reflux for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n 15 hexane : ethyl acetate = 10 : 1). The purified product was concentrated under reduced pressure to thereby obtain 19.7 g of oily yellow ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2 propoxyphenylamino)buta-2-enoic acid (yield: 99%). 'H-NMR (CDCl 3 ) dppm: 20 1.02 (3H, t, J=7.5 Hz), 1.28 (3H, t, 7.0 Hz), 1.74-1.88 (2H, m), 3.85 (2H, t, J=6.5 Hz), 4.17 (2H, q, J=7.0 Hz), 5.41 (1H, s), 6.77-6.97 (3H, m), 9.77 (1H, brs) Reference Example 71 25 5-Fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one Diphenyl ether (15 ml) was added to ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid (19.7 g, 59.0 mmol), and the mixture was stirred for 1.5 hours while heating under reflux. The reaction mixture was cooled 30 to room temperature, n-hexane was added, and the precipitate was collected by filtration. The substance remaining on the filter was washed with n-hexane, and dried to thereby obtain 16.2 g of powdery white 5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin- 4 one (yield: 94%). 35 'H-NMR (DMSO-d 6 ) dppm: WO 2008/150029 PCT/JP2008/060804 -60 1.00 (3H, t, J=7.5 Hz), 1.76-1.90 (2H, m), 4.07 (2H, t, J=6.5 Hz), 7.18-7.32 (3H, m), 12.26 (IH, brs) Reference Example 72 5 5-Fluoro-3-iodo-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one Potassium carbonate (3.73 g, 27 mmol) and iodide (6.85 g, 27 mmol) were added to a DMF solution (20 ml) of 5-fluoro-8 propoxy-2-trifluoromethyl-1H-quinolin-4-one (6.0 g, 20.7 mmol) in that order, and the resulting mixture was stirred at room 10 temperature for 1.5 hours. A saturated sodium sulfite aqueous solution (20 ml) and ethyl acetate were added to the reaction mixture, and the precipitated solid was collected by filtration. The filtrate was washed with water, and then dried over anhydrous sodium sulfate. The dried filtrate was concentrated under reduced 15 pressure. The residue and the substance collected by the advance filtration were combined, and dissolved in ethanol, and then concentrated. The residue was recrystallized from an ethyl acetate-n-hexane mixed solvent to thereby obtain 4.7 g of powdery white 5-fluoro-3-iodo-8-propoxy-2-trifluoromethyl-1H-quinolin-4 20 one (yield: 55%). 1 H-NMR (DMSO-d 6 ) dppm: 0.96 (3H, t, J=7.5 Hz), 1.70-1.80 (2H, m), 3.95 (2H, t, J=6.5 Hz), 6.64-6.85 (2H, m), 12.02 (lH, brs) 25 Reference Example 73 1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone Potassium carbonate (6.55 g, 47.4 mmol), cyclopentyl bromide (8.25 g, 55.3 mmol) and DMF (5 ml) were added to a DMF solution (10 ml) of 5'-bromo-2'-hydroxyacetophenone (8.5 g, 39.5 30 mmol), and the resulting mixture was stirred at 60 0 C for 4.5 hours. Potassium carbonate (3.0 g, 21.7 mmol) and cyclopentyl bromide (2.0 g, 13.4 mmol) were added to the resultant mixture, and stirred at 60 0 C for 9 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture 35 was extracted with ethyl acetate. The organic layer was washed WO 2008/150029 PCT/JP2008/060804 -61 with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane: ethyl acetate=9 : 1). The purified product was concentrated under reduced 5 pressure to thereby obtain 11.3 g of oily pale yellow 1-(5-bromo 2-cyclopentyloxyphenyl)ethanone (yield: 100%). IH-NMR (CDCl 3 ) dppm: 1.68-1.95 (8H, m), 2.58 (3H, s), 4.83-4.87 (1H, m), 6.83 (1H, d, J=8.9 Hz), 7.49 (lH, dd, J=2.6 Hz, 8.9 Hz), 7.82 (1H, d, J=2.6 10 Hz) Reference Example 74 1- (5-Bromo-2-cyclopentyloxyphenyl) ethanone oxime 1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone (5.0 g, 15 17.65 mmol) was dissolved in a mixed solvent of chloroform (18 ml) and methanol (70 ml). Hydroxylamine hydrochloride (1.88 g, 27.0 mmol) and pyridine (4.36 ml, 54.1 mmol) were added to the resulting solution, and the mixture was stirred for 6 hours while heating under reflux. The reaction mixture was cooled to room 20 temperature, and then concentrated under reduced pressure. 2N Hydrochloric acid (13.9 ml) was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated to 25 dryness under reduced pressure. The residue was washed with n hexane and dried to thereby obtain 4.6 g of powdery white 1-(5 bromo-2-cyclopentyloxyphenyl) ethanone oxime (yield: 87%). 1 H-NMR (CDCl 3 ) dppm: 1.65-1.90 (8H, m), 2.17 (3H, s), 4.72-4.76 (1H, m), 6.76 (1H, d, 30 J=8.4 Hz), 7.35-7.41 (2H, m), 7.99 (1H, brs) Reference Example 75 N-(5-Bromo-2-cyclopentyloxyphenyl)acetamide 1-(5-Bromo-2-cyclopentyloxyphenyl)ethanone oxime (4.56 35 g, 15.3 mmol) was suspended in acetonitrile (100 ml). Indium WO 2008/150029 PCT/JP2008/060804 -62 (III) chloride (507 mg, 2.29 mmol) was added thereto, and the resultant was heated under reflux for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was 5 extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane: ethyl acetate=8 : 1-->4 : 1). The purified product was concentrated under 10 reduced pressure to thereby obtain 3.41 g of oily pale yellow N (5-bromo-2-cyclopentyloxyphenyl)acetamide (yield: 75%). 'H-NMR (CDCl 3 ) dppm: 1.67-1.94 (8H, m), 2.18 (3H, s), 4.75-4.81 (1H, m), 6.72 (1H, d, J=8.7 Hz), 7.10 (1H, dd, J=2.3 Hz, 8.7 Hz), 7.67 (1H, brs), 8.55 15 (1H, d, J=2.3 Hz) Reference Example 76 5-Bromo-2-cyclopentyloxyaniline Concentrated hydrochloric acid (5.8 ml) was added to an 20 ethanol solution (100 ml) of N-(5-bromo-2 cyclopentyloxyphenyl) acetamide (3.4 g, 11.4 mmol), and the resulting mixture was stirred for 3 hours while heating under reflux. After the reaction mixture was cooled to room temperature, a 5N sodium hydroxide solution (14.2 ml) was added to obtain a pH 25 of 11. The resulting mixture was then extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (n-hexane: ethyl acetate=4: 1). The purified 30 product was concentrated under reduced pressure to thereby obtain 2.97 g of oily pale yellow 5-bromo-2-cyclopentyloxyaniline (yield: 100%). 1 H-NMR (CDCl 3 ) dppm: 1.62-1.89 (8H, m), 3.80 (2H, brs), 4.71-4.75 (1H, m), 6.61 (1H, d, 35 J=8.4 Hz), 6.75-6.81 (2H, m) WO 2008/150029 PCT/JP2008/060804 -63 Example 1 5-Fluoro-3-furan-3-yl-8-propoxy-1H-quinolin-4-one 5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (780 mg, 5 2.24 mmol) was suspended in a mixed solvent of toluene (10 ml) and methanol (1.6 ml), and furan-3-boronic acid (752 mg), tetrakis triphenylphosphine palladium (130 mg, 0.11 mmol), and a 2N sodium carbonate aqueous solution (2.25 ml) were added thereto in that order. The mixture was stirred under a nitrogen 10 atmosphere at 110 0 C for 20 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, the residue was then purified by silica gel column chromatography (dichloromethane 15 methanol = 60 : 1 -+ 50 : 1). The purified product was concentrated under reduced pressure and was recrystallized from ethanol to thereby obtain 180 mg of powdery pale yellow 5-fluoro 3-furan-3-yl-8-propoxy-1H-quinolin-4-one (yield: 58%). Melting point 214-215 0 C 20 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, J=7.3 Hz), 1.78-1.87 (2H, m), 4.09 (2H, t, J=6.4 Hz), 6.87-6.95 (2H, m), 7.13 (1H, dd, J=3.8 Hz, J= 8.8 Hz), 7.67 (1H, s), 8.11 (lH, s), 8.51 (lH, s), 11.50 (lH, brs) 25 The compounds of the following Examples 2 to 5 were prepared in the same manner as the above Example 1, using corresponding starting materials. Example 2 30 5-Fluoro-3-(3-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one Gray powder (ethanol) Melting point 194-195 0 C 'H-NMR (DMSO-d,) dppm: 1.03 (3H, t, J=7.3 Hz), 1.79-1.87 (2H, m), 3.84 (3H, s), 4.09 (2H, 35 t, J=6.4 Hz), 6.90 (lH, dd, J=8.7 Hz, J= 12.1 Hz), 7.12-7.19 (2H, WO 2008/150029 PCT/JP2008/060804 -64 m), 7.35-7.39 (1H, m), 7.56 (lH, dd, J=2.0 Hz, J=13.5 Hz), 7.87 (lH, s), 11.40 (1H, brs) Example 3 5 5-Fluoro-8-propoxy-3-thiophen-3-yl-lH-quinolin-4-one Pale brown powder (ethanol) Melting point 208-210 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.4 Hz), 1.75-1.89 (2H, m), 4.08 (2H, t, J=6.4 Hz), 10 6.90 (1H, dd, J=8.7 Hz, J=12.1 Hz), 7.13 (1H, dd, J=3.9 Hz, J= 8.8 Hz), 7.50-7.57 (2H, m), 8.14 (1H, s), 8.19-8.21 (1H, m), 11.42 (1H, brs) Example 4 15 3-(3-Chloro-4-methoxyphenyl)-5-fluoro-8-propoxy-lH-quinolin-4-one Pale yellow powder (ethanol) Melting point 217-218 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 3.85 (3H, s), 4.08 (2H, 20 t, J=6.4 Hz), 6.90 (1H, dd, J=8.8 Hz, J= 12.0 Hz), 7.10-7.15 (2H, m), 7.51 (1H, dd, J=2.1 Hz, J= 8.5 Hz), 7.74 (1H, d, J=2.1 Hz), 7.87 (1H, s), 11.45 (1H, brs) Example 5 25 5-Fluoro-8-propoxy-3-(4-trifluoromethoxyphenyl)-lH-quinolin-4-one Pale gray powder (ethanol) Melting point 212-214 0 C IH-NMR (DMSO-d 6 ) dppm: 1.03 (3H, t, J=7.3 Hz), 1.79-1.87 (2H, m), 4.09 (2H, t, J=6.4 Hz), 30 6.92 (1H, dd, J=8.8 Hz, J= 12.0 Hz), 7.16 (lH, dd, J=3.9 Hz, J=8.8 Hz), 7.35 (2H, d, J=8.5 Hz), 7.73 (2H, d, J=8.7 Hz), 7.91 (1H, s), 11.45 (1H, brs) Example 6 35 5-Fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one WO 2008/150029 PCT/JP2008/060804 -65 Amberlyst 15 (1.0 g, a product of Sigma Aldrich Corp.) was added to a benzene solution (150 ml) of 5-fluoro-2 propoxyaniline (16.25 g, 96.0 mmol) and ethyl a (hydroxymethylene)-4-methoxyphenyl acetate (21.34 g, 96.0 mmol). 5 The mixture was heated under reflux for 14 hours while using a Dean-Stark trap and being stirred. The reaction mixture was cooled to room temperature, the resin was removed by filtration, and the filtrate was concentrated under reduced pressure. Diphenyl ether (40 ml) was added to the residue, and the mixture 10 was heated using a mantle heater and stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature and purified directly by silica gel column chromatography (dichloromethane : methanol = 100 : 0 -+ 30 : 1 -+ 20 : 1). The purified product was concentrated under reduced pressure, and the 15 residue was recrystallized from ethanol to thereby obtain 5.28 g of powdery pale yellow 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H quinolin-4-one (yield: 17%). Melting point 196-197 0 C 1 H-NMR (DMSO-d 6 ) dppm: 20 1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 3.75 (3H, s), 4.07 (2H, t, J=6.4 Hz), 6.83-6.96 (3H, m), 7.11 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz), 7.81 (1H, s), 11.50 (1H, brs) The compounds of the following Examples 7 to 46 were 25 prepared in the same manner as the above Example 6, using corresponding starting materials. Example 7 5-Fluoro-3-(2-methoxyphenyl)-8-propoxy-1H-quinolin-4-one 30 White powder (ethyl acetate) Melting point 193-195 0 C IH-NMR (CDCl 3 ) dppm: 1.05 (3H, t, J=7.5 Hz), 1.82-1.97 (2H, m), 3.77 (3H, s), 4.05 (2H, t, J=6.3 Hz), 6.77-7.02 (4H, m), 7.26-7.29 (1H, m), 7.42-7.45 (1H, 35 m), 7.72-7.74 (1H, m), 8.83 (1H, brs) WO 2008/150029 PCT/JP2008/060804 -66 Example 8 3- (2, 4-Dimethoxyphenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one Pale yellow powder (ethyl acetate) 5 Melting point 116-118 0 C IH-NMR (CDCl 3 ) dppm: 1.07 (3H, t, J=7.5 Hz), 1.84-1.98 (2H, m), 3.76 (3H, s), 3.84 (3H, s), 4.06 (2H, t, J=7.5 Hz), 6.54-6.58 (2H, m), 6.77-6.92 (2H, m), 7.38-7.42 (lH, m), 7.72-7.75 (lH, m), 8.79 (1H, brs) 10 Example 9 5-Fluoro-8-isopropoxy-3- (4-methoxyphenyl) -1H-quinolin-4-one White powder (ethyl acetate) Melting point 193-194 0 C 15 1 H-NMR (CDCl 3 ) dppm: 1.39 (6H, d, J=5.0 Hz), 3.79 (3H, s), 4.58 (1H, q, J=5.0 Hz), 6.79-6.92 (4H, m), 7.54-7.57 (2H, m), 7.68-7.71 (1H, m), 8.80 (1H, brs) 20 Example 10 3- (2, 4-Dichlorophenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate) Melting point 256-259 0 C 1 H-NMR (DMSO-d 6 ) dppm: 25 1.01 (3H, t, J=7.5 Hz), 1.79-1.87 (2H, m), 4.08 (2H, t, J=6.3 Hz), 6.88-6.98 (1H, m), 6.96-7.72 (1H, m), 7.37-7.47 (2H, m), 7.65 7.67 (1H, m), 7.75-7.77 (lH, m), 11.42 (1H, brs) Example 11 30 8-Ethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one Pale yellow powder (ethyl acetate) Melting point 155-156 0 C H-NMR (CDCl 3 ) dppm: 1.46 (3H, t, J=7.5 Hz), 3.81 (3H, s), 4.14 (2H, q, J=7.5 Hz), 6.77-6.94 (4H, m), 7.54-7.60 (2H, m), 7.71 35 7.73 (1H, m), 9.02 (1H, brs) WO 2008/150029 PCT/JP2008/060804 -67 Example 12 3- (2, 4-Dimethoxyphenyl) -8-ethoxy-5-fluoro-lH-quinolin-4-one Pale yellow powder (ethyl acetate) 5 Melting point 154-155 0 C IH-NMR (CDCl 3 ) dppm: 1.44 (3H, t, J=7.5 Hz), 3.73 (3H, s), 3.81 (3H, s), 4.12 (2H, q, J= 7.5 Hz), 6.50-6.53 (2H, m), 6.54-6.89 (2H, m), 7.35-7.39 (1H, m), 7.69-7.72 (lH, m), 8.97 (1H, brs) 10 Example 13 3-(2,4-Dichlorophenyl)-8-ethoxy-5-fluoro-1H-quinolin-4-one Pale yellow powder (ethyl acetate) Melting point 236-237 0 C 15 1 H-NMR (DMSO-d 6 ) dppm: 1.40 (3H, t, J=7.5 Hz), 4.17 (2H, q, J=7.5 Hz), 6.88-7.00 (1H, m), 7.22-7.32 (1H, m), 7.38-7.45 (2H, m), 7.64-7.65 (1H, m), 7.74 7.75 (1H, m), 11.40 (1H, brs) 20 Example 14 5-Fluoro-3-(4-methoxyphenyl)-8-morpholin-4-yl-1H-quinolin-4-one Pale yellow powder (ethyl acetate) Melting point 249-251 0 C IH-NMR (CDCl 3 ) dppm: 25 2.75-3.22 (4H, m), 3.65-4.15 (4H, m), 6.85-6.93 (3H, m), 7.34 7.40 (1H, m), 7.54-7.58 (2H, m), 7.74-7.77 (1H, m), 10.02 (1H, brs) Example 15 30 5-Fluoro-3- (2-isopropoxy-4-methoxyphenyl) -8-propoxy-1H-quinolin 4-one White powder (ethyl acetate) Melting point 204-206 0 C 1 H-NMR (CDCl 3 ) dppm: 35 1.09 (3H, t, J=6.3 Hz), 1.23 (3H, s), 1.26 (3H, s), 1.87-2.01 (2H, WO 2008/150029 PCT/JP2008/060804 -68 m), 3.83 (3H, s), 4.08 (2H, t, J=6.3 Hz), 4,34-4.50 (1H, m), 6.55-6.60 (2H, m), 6.78-6.93 (2H, m), 7.50 (1H, d, J=7.5 Hz), 7.80 (lH, d, J=7.5 Hz), 8.73 (1H, brs) 5 Example 16 5-Fluoro-3-(4-methoxy-2-methylphenyl)-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate) Melting point 197-199 0 C 1 H-NMR (CDCl 3 ) dppm: 10 1.06 (3H, t, J=6.3 Hz), 1.80-2.00 (2H, m), 2.24 (3H, s), 3.80 (3H, s), 4.07 (2H, t, J=6.3 Hz), 6.70-6.94 (4H, m), 7.07 (1H, d, J=7.5 Hz), 7.54 (1H, d, J=7.5 Hz), 8.80 (1H, brs) Example 17 15 5-Fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate-ethanol) Melting point 230-232 0 C 1H-NMR (CDCl 3 ) dppm: 1.05 (3H, t, J=7.5 Hz), 1.80-2.00 (2H, m), 3.80 (3H, s), 4.06 (2H, 20 t, J=7.5 Hz), 6.64-6.93 (4H, m), 7.53-7.60 (1H, m), 7.74-7.78 (1H, m), 8.86 (1H, brs) Example 18 5-Fluoro-3-(4-methoxyphenyl)-8-pyrrolidin-1-yl-1H-quinolin-4-one 25 Pale brown powder (ethyl acetate-n-hexane) Melting point 100-105 0 C 1 H-NMR (CDCl 3 ) dppm: 1.90-2.08 (4H, m), 3.01-3.20 (4H, m), 3.81 (3H, s), 6.81-6.94 (3H, m), 7.29-7.34 (1H, m), 7.55-7.60 (2H, m), 7.74-7.76 (1H, m), 9.41 30 (1H, brs) Example 19 3-(4-Ethoxy-2-methoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one Pale brown powder (ethyl acetate) 35 Melting point 118-120 0
C
WO 2008/150029 PCT/JP2008/060804 -69 1 H-NMR (CDCl 3 ) dppm: 1.06 (3H, t, J=7.5 Hz), 1.39 (3H, t, J=7.5 Hz), 1.83-1.98 (2H, m), 3.75 (3H, s), 4.00-4.14 (4H, m), 6.51-6.55 (2H, m), 6.76-6.91 (2H, m), 7.38 (1H, d, J=6.2 Hz), 7.72 (1H, d, J=6.2 Hz), 8.65 (1H, 5 brs) Example 20 5-Fluoro-3- (4-isopropoxy-2-methoxyphenyl) -8-propoxy-1H-quinolin 4-one 10 White powder (ethyl acetate-n-hexane) Melting point 113-115 0 C 1 H-NMR (CDCl 3 ) dppm: 1.04 (3H, t, J=7.5 Hz), 1.33 (3H, s), 1.36 (3H, s), 1.80-1.95 (2H, m), 3.72 (3H, s), 4.03 (2H, t, J=7.5 Hz), 4.50-4.71 (1H, m), 15 6.49-6.53 (2H, m), 6.78-6.86 (2H, m), 7.34-7.38 (1H, m), 7.42 7.74 (1H, m), 8.82 (1H, brs) Example 21 5,6-Difluoro-3-(4-methoxyphenyl)- 8 -propoxy-1H-quinolin-4-one 20 Pale brown powder (ethyl acetate-n-hexane) Melting point 198-200 0 C 'H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 3.75 (3H, s), 4.11 (2H, t, J=6.4 Hz), 6.93 (2H, d, J=8.8 Hz), 7.38 (1H, dd, J=6.5 Hz, J= 25 12.3 Hz), 7.54 (2H, d, J=8.8 Hz), 7.81 (1H, s), 11.50 (lH, brs) Example 22 8-Bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one Pale yellow powder (ethyl acetate) 30 Melting point 134-135 0 C H-NMR (DMSO-d 6 ) dppm: 3.78 (3H, s), 6.94-7.02 (3H, m), 7.52 (2H, d, J=6.3 Hz), 7.84 (1H, s), 7.89-8.00 (1H, m), 11.20 (1H, brs) 35 Example 23 WO 2008/150029 PCT/JP2008/060804 -70 5-Fluoro-3- (4-methoxyphenyl) -8-(pyrrolidin-1-carbonyl) -lH quinolin-4-one Orange powder (ethyl acetate) Melting point 236-237 0 C 5 'H-NMR (DMSO-d 6 ) dppm: 1.77-1.91 (4H, m), 3.29-3.34 (2H, m), 3.54-3.59 (2H, m), 3.76 (3H, s), 6.94 (2H, d, J=8.7 Hz), 7.02 (1H, dd, J=8.3 Hz, J=11.8 Hz), 7.53 (2H, d, J=8.7 Hz), 7.71 (1H, dd, J=5.1 Hz, J=8.3 Hz), 7.88 (1H, s), 11.26 (lH, s) 10 Example 24 8-Cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4 one Pale yellow powder (ethyl acetate-ethanol) 15 Melting point 190-191 0 C 1 H-NMR (DMSO-d 6 ) dppm: 0.33-0.39 (2H, m), 0.55-0.62 (2H, m), 1.26-1.34 (1H, m), 3.75 (3H, s), 3.99 (2H, d, J=7.0 Hz), 6.83-6.95 (3H, m), 7.12 (1H, dd, J=3.8 Hz, J= 8.8 Hz), 7.53 (2H, d, J=8.6 Hz), 7.82 (lH, s), 11.34 20 (lH, brs) Example 25 8- (N-Cyclohexyl-N-methylamino) -5-fluoro-3- (4-methoxyphenyl) -1H quinolin-4-one 25 Pale yellow powder (ethyl acetate) Melting point 224-225 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.00-1.24 (5H, m), 1.53-1.99 (5H, m), 2.65 (3H, s), 3.78 (3H, s), 6.92-6.99 (3H, m), 7.50-7.57 (3H, s), 7.87 (1H, s), 10.93 (lH, 30 brs) Example 26
N-{
3 -[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8 yloxy]propyllacetamide 35 Pale brown powder (ethanol) WO 2008/150029 PCT/JP2008/060804 -71 Melting point 229-231 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.80 (3H, s), 1.91-1.96 (2H, m), 3.24-3.31 (2H, m), 3.74 (3H, s), 4.12 (2H, t, J=5.6 Hz), 6.84-7.13 (4H, m), 7.53 (2H, d, J=8.6 Hz), 5 7.83 (lH, s), 8.01 (1H, brs), 11.40 (1H, brs) Example 27 N-{3-[5-Fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8 yloxy]propyl methanesulfonamide 10 Pale brown powder (ethanol) Melting point 120-121 0 C 'H-NMR (DMSO-d 6 ) dppm: 1.96-2.06 (2H, m), 2.88 (3H, s), 3.10-3.30 (2H, m), 3.75 (3H, s), 4.18 (2H, t, J=5.9 Hz), 6.85-6.95 (3H, m), 7.00-7.16 (2H, m), 15 7.54 (2H, d, J=8.7 Hz), 7.82 (1H, s), 11.34 (1H, brs) Example 28 5-Fluoro-8-(N-isobutyl-N-methylamino)-3-(4-methoxyphenyl)-lH quinolin-4-one 20 White powder (ethyl acetate) Melting point 144-145 0 C 'H-NMR (DMSO-d 6 ) dppm: 0.86 (3H, s), 0.91 (3H, s), 1.61-1.67 (1H, m), 2.61 (3H, s), 2.80 (2H, d, J=6.75 Hz), 3.79 (3H, s), 6.91-6.99 (3H, m), 7.46-7.57 25 (3H, m), 7.88 (1H, s), 11.02 (1H, brs) Example 29 5-Fluoro-8-(N-isopropyl-N-methylamino)-3-(4-methoxyphenyl)-1H quinolin-4-one 30 White powder (ethyl acetate) Melting point 267-269 0 C 1H-NMR (DMSO-d 6 ) dppm: 1.04 (3H, s), 1.06 (3H, s), 2.62 (3H, s), 3.10-3.18 (1H, m), 3.76 (3H, s), 6.90-6.98 (3H, m), 7.47-7.55 (3H, m), 7.85 (1H, s), 35 10.94 (1H, brs) WO 2008/150029 PCT/JP2008/060804 -72 Example 30 5-Fluoro-3-(4-methoxyphenyl)-8-(N-methyl-N-propylamino)-lH quinolin-4-one 5 Pale yellow powder (ethyl acetate) Melting point 145-146 0 C 1H-NMR (DMSO-d 6 ) dppm: 0.79 (3H, t, J=7.5 Hz), 1.31-1.45 (2H, m), 2.63 (3H, s), 2.85 (2H, t, J=7.5 Hz), 3.76 (3H, s), 6.89-6.97 (3H, m), 7.43-7.54 (3H, m), 10 7.82 (1H, s), 11.07 (1H, brs) Example 31 5-Fluoro-3- (4-methoxyphenyl) -8- (4,4,4-trifluorobutoxy) -1H quinolin-4-one 15 White powder (ethyl acetate) Melting point 171-172 0 C 1 H-NMR(DMSO-d) dppm: 1.99-2.08 (2H, m), 2.48-2.61 (2H, m), 3.74 (3H, s), 4.17 (2H, t, J=5.9 Hz), 6.84-6.94 (3H, m), 7.11 (lH, dd, J=3.8 Hz, J=8.8 Hz), 20 7.53 (2H, d, J=8.7 Hz), 7.82 (1H, s), 11.40 (1H, brs) Example 32 1-{3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinolin-8 yloxylpropyl}-1, 3,3-trimethyl urea 25 Brown amorphous solid (diethyl ether) 'H-NMR (DMSO-d 6 ) dppm: 2.00-2.05 (2H, m), 2.63 (6H, s), 2.74 (3H, s), 3.20-3.40 (2H, m), 3.76 (3H, s), 4.12 (2H, t, J=6.0 Hz), 6.85-6.96 (3H, m), 7.14 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.81 (lH, s), 30 11.40 (lH, brs) Example 33 3-(4-Ethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one Pale yellow powder (ethyl acetate) 35 Melting point 203-205 0
C
WO 2008/150029 PCT/JP2008/060804 -73 'H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.13 (3H, t, J=7.0 Hz), 1.76-1.91 (2H, m), 3.99-4.13 (4H, m), 6.84-6.94 (3H, m), 7.12-7.17 (lH, m), 7.50 (2H, d, J=7.5 Hz), 7.79 (1H, s), 11.25 (1H, brs) 5 Example 34 5-Fluoro-8- [N-(2-methoxyethyl) -N-methylaminol-3-(4 methoxyphenyl) -1H-quinolin- 4-one hydrochloride Pale yellow powder (ethyl acetate) 10 Melting point 100-101 0 C 1H-NMR (DMSO-d 6 ) dppm: 2.78(3H, s), 3.08 (2H, t, J=5.3 Hz), 3.33 (3H, s), 3.49(2H, t, J=5.3 Hz), 3.81 (3H, s), 6.94-7.02 (3H, m), 7.50-7.62 (3H, m), 8.00 (1H, s), 11.16 (1H, brs) 15 Example 35 3-( 4 -Cyclopropylmethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4 one White powder (ethyl acetate) 20 Melting point 162-163'C 'H-NMR (DMSO-d 6 ) dppm: 0.30-0.35 (2H, m), 0.54-0.58 (2H, m), 1.01 (3H, t, J=7.5 Hz), 1.10-1.30 (1H, m), 1.72-1.91 (2H, m), 3.80 (2H, d, J=7.0 Hz), 4.07 (2H, t, J=6.4 Hz), 6.84-6.93 (3H, m), 7.11-7.16 (1H, m), 25 7.50 (2H, d, J= 8.8 Hz), 7.79 (1H, s), 11.25 (1H, brs) Example 36 5-Fluoro-8-(2-methoxyethoxy)-3-(4-methoxyphenyl)-lH-quinolin-4 one 30 Pale yellow powder (ethyl acetate) Melting point 142-144 0 C 'H-NMR (DMSO-d 6 ) dppm: 3.31 (3H, s), 3.70-3.80 (2H, m), 3.75 (3H, s), 4.20-4.30 (2H, m), 6.84-6.94 (3H, m), 7.16 (lH, dd, J=3.6 Hz, J=8.7 Hz), 7.53 (2H, d, 35 J=8.4 Hz), 7.82 (1H, s), 11.10 (lH, brs) WO 2008/150029 PCT/JP2008/060804 -74 Example 37 8-Cyclopentyloxy-5-fluoro-3 - (4-methoxyphenyl) -1H-quinolin-4 -one Pale yellow powder (ethyl acetate) 5 Melting point 213-215 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.50-1.70 (2H, m), 1.71-2.00 (6H, m), 3.75 (3H, s), 4.92-4.95 (1H, m), 6.83-6.95 (3H, m), 7.09 (1H, dd, J=3.9 Hz, J= 8.8 Hz), 7.53 (2H, d, J=8.6 Hz), 7.80 (lH, s), 11.20 (IH, brs) 10 Example 38 5-Fluoro-3-(4-methylsulfanylphenyl)-8-propoxy-1H-quinolin-4-one Pale yellow powder (ethyl acetate) Melting point 198-199 0 C 15 'H-NMR (CDCl 3 ) dppm: 1.07 (3H, t, J=7.4 Hz), 1.85-2.04 (2H, m), 2.50 (3H, s), 4.07 (2H, t, J=6.6 Hz), 6.80-6.94 (2H, m), 7.27-7.31 (2H, m), 7.56 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=8.2 Hz), 8.81 (lH, brs) 20 Example 39 5-Fluoro-3- (4-methoxyphenyl) -8- (tetrahydrofuran-2-ylmethoxy) -1H quinolin-4-one Pale yellow powder (ethyl acetate) Melting point 108-110 0 C 25 1 H-NMR (DMSO-d 6 ) dppm: 1.67-1.75 (1H, m), 1.81-1.90 (2H, m), 2.02-2.09 (1H, m), 3.65 3.83 (2H, m), 3.75 (3H, s), 4.10 (2H, d, J=4.6 Hz), 4.25-4.29 (lH, m), 6.84-6.95 (3H, m), 7.17 (1H, dd, J=3.8 Hz, J=8.8 Hz), 7.53 (2H, d, J=8.7 Hz), 7.82 (1H, s), 11.20 (1H, brs) 30 Example 40 5-Fluoro-3-(4-methoxyphenyl)-8-propylsulfanyl-1H-quinolin-4-one White powder (ethyl acetate) Melting point 173-174 0 C 35 1 H-NMR (DMSO-d 6 ) dppm: WO 2008/150029 PCT/JP2008/060804 -75 0.90 (3H, t, J=7.3 Hz), 1.40-1.52 (2H, m), 2.79 (2H, t, J=7.2 Hz), 3.77 (3H, s), 6.93-7.04 (3H, m), 7.51-7.55 (2H, m), 7.79-7.87 (2H, m), 11.24 (1H, brs) 5 Example 41 8-Cyclobutylmethoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4 one Pale yellow powder (ethyl acetate) Melting point 193-194 0 C 10 'H-NMR (DMSO-d 6 ) dppm: 1.79-1.93 (4H, m), 2.04-2.09 (2H, m), 2.76-2.81 (1H, m), 3.74 (3H, s), 4.08 (2H, d, J=6.8 Hz), 6.83-6.93 (3H, m), 7.11 (1H, dd, J=3.8 Hz, J=8.8 Hz), 7.52 (2H, d, J=8.6 Hz), 7.82 (1H, s), 11.20 (1H, brs) 15 Example 42 8-tert-Butoxy-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one Pale brown powder (ethyl acetate-diethyl ether) Melting point 206-208 0 C 20 1 H-NMR (DMSO-d 6 ) dppm: 1.40 (9H, s), 3.76 (3H, s), 6.84-6.96 (3H, m), 7.31 (1H, dd, J=4.3 Hz, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.82 (1H, s), 10.95 (1H, brs) 25 Example 43 5-Fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one Pale dark brown powder (ethyl acetate) 1 H-NMR (DMSO-d 6 ) dppm: 3.76 (3H, s), 3.95 (3H, s), 6.87-6.95 (3H, m), 7.15(1H, dd, J=3.8 30 Hz, J= 8.8 Hz), 7.54 (2H, d, J=8.7 Hz), 7.76 (1H, s), 11.50 (1H, brs) Example 44 5-Fluoro-8-methoxymethoxy-3-(4-methoxyphenyl)-lH-quinolin-4-one 35 Pale dark brown powder (dichloromethane-methanol) WO 2008/150029 PCT/JP2008/060804 -76 H-NMR (CDCl 3 ) dppm: 3.44 (3H, s), 3.76 (3H, s), 5.20 (2H, s), 6.76-6.87 (3H, m), 7.18-7.23 (1H, m), 7.52 (2H, d, J=7.8 Hz), 7.69 (1H, s), 9.68 (1H, brs) 5 Example 45 8-(3-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin 4-one Dark brown amorphous solid 10 1 H-NMR (DMSO-d 6 ) dppm: 2.08-2.13 (2H, m), 3.68 (2H, t, J=6.2Hz), 3.77 (3H, s), 4.22 (2H, t, J=6.0 Hz), 4.48 (2H, s), 6.84-6.97 (3H, m), 7.13-7.18 (1H, m), 7.21-7.29 (5H, m), 7.55 (2H, d, J=8.7 Hz), 7.76 (1H, s), 11.25 (1H, brs) 15 Example 46 8-(2-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin 4-one Dark brown amorphous solid 20 1 H-NMR (DMSO-d 6 ) dppm: 1.32 (3H, d, J=6.2Hz), 3.76 (3H, s), 3.98-4.24 (3H, m), 4.54-4.69 (2H, m), 6.84-6.96 (3H, m), 7.16-7.30 (6H, m), 7.54 (2H, d, J=8.7 Hz), 7.78 (1H, s), 11.19 (1H, brs) 25 Example 47 8-Cyclopropylmethoxy-5-fluoro-3-(4-methoxyphenyl)-2-methyl-1H quinolin-4-one Amberlyst 15 (350 mg, a product of Sigma Aldrich Corp.) was added to a benzene solution (40 ml) of 2-cyclopropylmethoxy 30 5-fluoroaniline (760 mg, 4.2 mmol) and ethyl a-acetyl-4 methoxyphenyl acetate (1.0 g, 4.2 mmol), and the mixture was heated under reflux for 19 hours while using a Dean-Stark trap and being stirred. The reaction mixture was cooled to room temperature, the resin was removed by filtration, and the 35 filtrate was concentrated under reduced pressure. Diphenyl ether WO 2008/150029 PCT/JP2008/060804 -77 (2.2 ml) was added to the residue, and the mixture was heated using a mantle heater and then stirred for 1 hour under reflux. The reaction mixture was cooled to room temperature and purified directly by silica gel column chromatography (dichloromethane 5 methanol = 80 : 1 - 60 : 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 120 mg of powdery pale yellow 8-cyclopropylmethoxy-5-fluoro-3-(4 methoxyphenyl) -2-methyl-1H-quinolin-4-one (yield: 8%). 10 Melting point 167-169 0 C IH-NMR (DMSO-d 6 ) dppm: 0.35-0.39 (2H, m), 0.54-0.61 (2H, m), 1.31-1.37 (1H, m), 2.23 (3H, s), 3.76 (3H, s), 4.02 (2H, d, J=7.0 Hz), 6.80-6.94 (3H, m), 7.08-7.18 (3H, m), 10.62 (1H, brs) 15 The compound of the following Example 48 was prepared in the same manner as the above Example 47, using corresponding starting materials. 20 Example 48 2-Ethyl-5-fluoro-3- (4-methoxyphenyl) -8-propoxy-1H-quinolin-4-one Pale brown powder (ethyl acetate-n-hexane) Melting point 169-171 0 C IH-NMR (DMSO-d 6 ) dppm: 25 0.98-1.05 (6H, m), 1.80-1.89 (2H, m), 2.56 (2H, t, J=7.5 Hz), 3.77 (3H, s), 4.13 (2H, t, J=6.6 Hz), 6.81-6.95 (3H, m), 7.05 7.17 (3H, m), 10.40 (lH, brs) Example 49 30 5-Fluoro-8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one 5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (600 mg, 1.73 mmol) was suspended in 1,2-dimethoxyethane (12 ml). 3 pyridine boronic acid (752 mg), 1,1' bis(diphenylphosphino)ferrocene dichloro palladium(II) 35 dichloromethane complex (PdCl 2 (DPPF)) (76 mg, 0.093 mmol), and 2N WO 2008/150029 PCT/JP2008/060804 -78 sodium carbonate aqueous solution (2.54 ml) were added to the resulting suspension in that order. The mixture was stirred at 90 0 C for 2 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added, and the 5 resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane : methanol = 15 : 1). The purified product was concentrated under reduced pressure, and then recrystallized from 10 ethanol to thereby obtain 185 mg of powdery pale brown 5-fluoro 8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one (yield: 36%). Melting point 234-236 0 C IH-NMR (DMSO-d 6 ) dppm: 1.01 (3H, t, J=7.3 Hz), 1.77-1.86 (2H, m), 4.08 (2H, t, J=6.4 Hz), 15 6.93 (1H, dd, J=8.8 Hz, J=12.0 Hz), 7.13-7.18 (1H, m), 7.37-7.42 (1H, m), 7.97 (1H, s), 8.01-8.05 (1H, m), 8.44-8.46 (1H, m), 8.77 (1H, d, J=2.1 Hz), 11.55 (1H, brs) The compounds of the following Examples 50 to 66 were 20 prepared in the same manner as the above Example 49, using corresponding starting materials. Example 50 3-(4-Ethoxy-3-fluorophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one 25 Pale yellow powder (ethanol) Melting point 176-177 0 C IH-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.33 (3H, t, J=6.9 Hz), 1.75-1.89 (2H, m), 4.05-4.14 (4H, m), 6.90 (1H, dd, J=8.7 Hz, J=12.1 Hz), 7.09-7.16 30 (2H, m), 7.32-7.36 (1H, m), 7.52-7.58 (1H, m), 7.87 (1H, s), 11.45 (1H, s) Example 51 5-Fluoro-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one 35 Pale brown powder (ethanol) WO 2008/150029 PCT/JP2008/060804 -79 Melting point 259-261 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.78-1.86 (2H, m), 4.09 (2H, t, J=6.4 Hz), 6.96 (1H, dd, J=8.8 Hz, J=12.0 Hz), 7.19 (1H, dd, J=3.8 Hz, J=8.8 5 Hz), 7.71 (2H, d, J=6.1 Hz), 8.06 (1H, s), 8.52 (2H, d, J=6.1 Hz), 11.50 (1H, brs) Example 52 5-Fluoro-3-(4-phenoxyphenyl)-8-propoxy-1H-quinolin-4-one 10 Pale brown powder (ethanol) Melting point 228-230 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.01 (3H, t, J=7.3 Hz), 1.77-1.85 (2H, m), 4.07 (2H, t, J=6.2Hz), 6.90 (1H, dd, J=8.8 Hz, J=12.lHz), 6.97-7.02 (4H, m), 7.10-7.15 15 (2H, m), 7.34-7.63 (4H, m), 7.88 (1H, s), 11.40 (1H, brs) Example 53 3-(4-Ethylphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate) 20 Melting point 153-154 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.17 (3H, t, J=7.5 Hz), 1.78-1.86 (2H, m), 2.59 (2H, q, J=7.5 Hz), 4.08 (2H, t, J=6.4 Hz), 6.89 (1H, dd, J=8.8 Hz, J= 12.lHz), 7.10-7.21 (3H, m), 7.50 (2H, d, J=8.0 Hz), 25 7.83 (1H, s), 11.40 (1H, brs) Example 54 3-(4-Acetylphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one Pale red powder (ethyl acetate) 30 Melting point 180-181 0 C 1H-NMR (DMSO-d 6 ) dppm: 0.95 (3H, t, J=7.5 Hz), 1.71-1.83 (2H, m), 2.51 (3H, m), 4.02 (2H, t, J=6.6 Hz), 6.84-6.91 (1H, m), 7.10-7.14 (1H, m), 7.72 (2H, d, J=8.4 Hz), 7.87-7.90 (3H, m), 11.40 (1H, brs) 35 WO 2008/150029 PCT/JP2008/060804 -80 Example 55 Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl) benzoate White powder (ethyl acetate) 5 Melting point 201-202 0 C IH-NMR (DMSO-d 6 ) dppm: 1.01 (3H, t, J=7.3 Hz), 1.77-1.91 (2H, m), 3.86 (3H, s), 4.09 (2H, t, J=6.5 Hz), 6.90-6.99 (1H, m), 7.17-7.22 (1H, m), 7.80 (2H, d, J=8.5 Hz), 7.94-7.98 (3H, m), 11.48 (1H, brs) 10 Example 56 5-Fluoro-8-propoxy-3-[4-(pyrrolidine-1-carbonyl)phenyl]-1H quinolin-4-one Pale red powder (ethyl acetate) 15 Melting point 236-237 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.4 Hz), 1.79-1.89 (6H, m), 3.43-3.49 (4H, m), 4.08 (2H, t, J=6.5 Hz), 6.89-6.97 (1H, m), 7.15-7.20 (1H, m), 7.51 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.6 Hz), 7.90 (1H, s), 20 11.40 (1H, brs) Example 57 4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)-N,N dimethylbenzamide 25 Pale brown powder (ethyl acetate) Melting point 235-237 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.4 Hz), 1.80-1.89 (2H, m), 2.97 (6H, s), 4.08 (2H, t, J=6.4 Hz), 6.89-6.93 (1H, m), 7.15-7.20(1H, m), 7.39 (2H, d, 30 J=8.0 Hz), 7.67 (2H, d, J=8.0 Hz), 7.90 (1H, s), 11.41 (1H, brs) Example 58 5-Fluoro-3-furan-2-yl-8-propoxy-1H-quinolin-4-one Pale brown powder (ethyl acetate) 35 Melting point 210-212 0
C
WO 2008/150029 PCT/JP2008/060804 -81 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.4 Hz), 1.78-1.90 (2H, m), 4.10 (2H, t, J=6.6 Hz), 6.54-6.56 (1H, m), 6.90-6.99 (1H, m), 7.15-7.21 (2H, m), 7.64 7.65 (1H, m), 8.20 (1H, s), 11.47 (1H, brs) 5 Example 59 5-Fluoro-8-propoxy-3-thiophen-2-yl-1H-quinolin-4-one Pale red powder (ethyl acetate) Melting point 211-213 0 C 10 1H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.5 Hz), 1.78-1.90 (2H, m), 4.10 (2H, t, J=6.5 Hz), 6.92-7.20 (3H, m), 7.41-7.59 (2H, m), 8.34 (1H, s), 11.63 (1H, brs) 15 Example 60 3-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)thiophene-2 carbaldehyde White powder (ethyl acetate) Melting point 190-191 0 C 20 H-NMR (DMSO-d 6 ) dppm: 1.01 (3H, t, J=7.4 Hz), 1.79-1.88 (2H, m), 4.08 (3H, t, J=6.5 Hz), 6.92-7.00 (1H, m), 7.18-7.23 (1H, m), 7.32 (1H, d, J=5.0 Hz), 7.98 (1H, s), 8.04-8.06 (1H, m), 9.73 (1H, s), 11.40 (1H, brs) 25 Example 61 3-(4-Dimethylaminophenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate) Melting point 206-207 0 C 1 H-NMR (DMSO-d 6 ) dppm: 30 1.01 (3H, t, J=7.4 Hz), 1.79-1.88 (2H, m), 2.90 (6H, s), 4.07 (2H, t, J=6.4 Hz), 6.71 (2H, d, J=9.0 Hz), 6.82-6.90 (1H, m), 7.09 7.14 (1H, m), 7,45 (2H, d, J=9.0 Hz), 7.76 (1H, s), 11.18 (1H, brs) 35 Example 62 WO 2008/150029 PCT/JP2008/060804 -82 3-(3, 4-Dimethoxyphenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one Pale red powder (ethyl acetate) Melting point 217-218 0 C IH-NMR (DMSO-d 6 ) dppm: 5 1.02 (3H, t, J=7.5 Hz), 1.78-1.88 (2H, m), 3.76 (6H, s), 4.07 (2H, t, J=6.4 Hz), 6.85-6.97 (2H, m), 7.08-7.16 (2H, m), 7.30 (1H, s), 7.82 (1H, s), 11.28 (1H, brs) Example 63 10 5-Fluoro-3-(6-methoxypyridiri-3-yl)-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate) Melting point 215-216 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.5 Hz), 1.77-1.91 (2H, m), 3.86 (3H, s), 4.08 (2H, 15 t, J=6.3 Hz), 6.81-6.96 (2H, m), 7.14-7.19 (1H, m), 7.77-7.99 (2H, m), 8.35 (lH, s), 11.39 (1H, brs) Example 64 3-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-8-propoxy-lH-quinolin-4 20 one Pale red powder (ethyl acetate) Melting point 198-199 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.01 (3H, t, J=7.3 Hz), 1.76-1.90 (2H, s), 3.83 (3H, s). 3.89 (3H, 25 s), 4.07 (2H, t, J=6.3 Hz), 6.39 (1H, d, J=7.1 Hz), 6.86-6.94 (lH, m), 7.13-7.17 (1H, m), 7.68 (1H, d, J=7.1 Hz), 7.81 (1H, s), 11.23 (1H, brs) Example 65 30 3-(2,5-Dimethoxyphenyl)-5-fluoro-8-propoxy-1H-quinolin-4-one Pale red powder (ethyl acetate) Melting point 156-157-C 1 H-NMR (DMSO-d 6 ) dppm: 1.03 (3H, t, J=7.3 Hz), 1.80-1.90 (2H, m), 3.65 (3H, s), 3.71 (3H, 35 s), 4.09 (2H, t, J=6.3 Hz), 6.87-6.91 (4H, m), 6.94-6.95 (lH, m), WO 2008/150029 PCT/JP2008/060804 -83 7.73 (lH, s), 11.18 (1H, brs) Example 66 8-Cyclopropylmethoxy-1-ethyl-5-fluoro-3- (4-methoxyphenyl) -1H 5 quinolin-4-one Brown powder (ethyl acetate-n-hexane) Melting point 150-152'C IH-NMR (DMSO-d 6 ) dppm: 0.34-0.38 (2H, m), 0.57-0.64 (2H, m,), 1.27-1.39 (4H, m), 3.75 (3H, 10 s), 3.92 (2H, d, J=7.2Hz), 4.60 (2H, q, J=6.8 Hz), 6.91-6.99 (3H, m), 7.17 (1H, dd, J=4.5 Hz, J=8.9 Hz), 7.60 (2H, d, J=8.7 Hz), 7.98 (1H, s) Example 67 15 5-Fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one 5-Fluoro-3-iodo-2-methyl-8-propoxy-1H-quinolin-4-one (400 mg, 1.11 mnol), 4-methoxyphenyl boronic acid (504 mg, 3.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloro palladium (II)-dichloro methane complex (PdCl 2 (DPPF)) (100 mg, 0.12 mmol) 20 and a 2N sodium carbonate aqueous solution (1 ml) were added to 1,2-dimethoxyethane (3 ml), and the mixture was heated at 170'C for 10 minutes (microwave reactor). The reaction mixture was cooled to room temperature, and filtration with Celite was carried out. The filtrate was extracted with dichloromethane, and 25 washed with water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane : methanol = 100 : 0 -+ 40 : 1). The purified product was concentrated under reduced pressure, and the residue 30 was recrystallized from ethyl acetate to thereby obtain 230 mg of powdery white 5-fluoro-3- (4-methoxyphenyl) -2-methyl-8-propoxy-1H quinolin-4-one (yield: 61%). Melting point 211-212 0 C 1 H-NMR (DMSO-d 6 ) dppm: 35 0.98 (3H, t, J=7.3 Hz), 1.79-1.90 (2H, m), 2.23 (3H, s), 3.76 (3H, WO 2008/150029 PCT/JP2008/060804 -84 s), 4.10 (2H, t, J=6.5 Hz), 6.93-6.95 (2H, m), 7.07-7.09 (2H, m), 7.72-7.73 (1H, m), 7.83 (1H, s), 10.50 (1H, brs) The compounds of the following Examples 68 to 85 were 5 prepared in the same manner as the above Example 67, using corresponding starting materials. Example 68 5-Fluoro-2-methyl-8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one 10 White powder (ethyl acetate) Melting point 190-192 0 C IH-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.5 Hz), 1.77-1.89 (2H, m), 2.27 (3H, s), 4.12 (2H, t, J=6.7 Hz), 6.85-6.93 (1H, m), 7.16-7.21 (1H, m), 7.38-7.43 (1H, 15 m), 7.63-7.67 (1H, m). 8.40-8.50 (2H, m), 10.70 (1H, brs) Example 69 5-Fluoro-2-methyl-8-propoxy-3-pyridin-4-yl-1H-quinolin-4-one White powder (ethyl acetate) 20 Melting point 265-266 0 C 1 H-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.5 Hz), 1.78-1.92 (2H, m), 2.28 (3H, s), 4.12 (2H, t, J=6.8 Hz), 6.86-6.94 (1H, m), 7.17-7.21 (1H, m), 7.25 (2H, d, J=6.0 Hz), 8.55 (2H, d, J=6.0 Hz), 10.72 (1H, brs) 25 Example 70 5-Fluoro-2-methyl-8-propoxy-3-(4-trifluoromethoxyphenyl)-1H quinolin-4-one Pale yellow powder (ethyl acetate) 30 Melting point 167-168 0 C 1 H-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.3 Hz), 1.78-1.92 (2H, m), 2.25 (3H, s), 4.10 (2H, t, J=6.6 Hz), 6.83-6.92 (1H, m), 7.15-7.20 (1H, m), 7.31-7.38 (4H, m), 10.64 (lH, brs) 35 WO 2008/150029 PCT/JP2008/060804 -85 Example 71 3-(4-Ethylphenyl)-5-fluoro-2-methyl-8-propoxy-1H-quinolin-4-one Pale red powder (ethyl acetate) Melting point 221-222'C 5 'H-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.3 Hz), 1.18 (3H, t, J=7.5 Hz), 1.80-1.89 (2H, m), 2.23 (3H, s), 2.58 (2H, q, J=7.5 Hz), 4.10 (2H, t, J=6.6 Hz), 6.82-6.89 (1H, m), 7.08-7.22 (5H, m), 10.53 (1H, brs) 10 Example 72 5-Fluoro-2-methyl-8-propoxy-3-thiophen-2-yl-1H-quinolin-4-one White powder (ethyl acetate) Melting point 233-234 0 C H-NMR (DMSO-d 6 ) dppm: 15 0.98 (3H, t, J=7.3 Hz), 1.77-1.89 (2H, m), 2.46 (3H, s), 4.11 (2H, t, J=6.8 Hz), 6.86-7.20 (4H, m), 7.52-7.55 (1H, m), 10.70 (1H, brs) Example 73 20 3-(4-Dimethylaminophenyl)-5-fluoro-2-methyl-8-propoxy-1H quinolin-4-one White powder (ethyl acetate) Melting point 255-257 0 C 'H-NMR (DMSO-d 6 ) dppm: 25 1.00 (3H, t, J=7.5 Hz), 1.80-1.90 (2H, m), 2.26 (3H, s), 2.91 (6H, s), 4.11 (2H, t, J=6.6 Hz), 6.72 (2H, d, J=8.7 Hz), 6.80-6.89 (1H, m), 7.00 (2H, d, J=8.7 Hz), 7.11-7.17 (1H, m), 10.45 (1H, brs) Example 74 30 5-Fluoro-3-(4-fluorophenyl)-2-methyl-8-propoxy-1H-quinolin-4-one Pale brown powder (ethyl acetate) Melting point 196-197 0 C IH-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.3 Hz), 1.80-1.91 (2H, m), 2.25 (3H, s), 4.12 (2H, 35 t, 6.8 Hz), 6.84-6.92 (1H, m), 7.15-7.29 (5H, m), 10.06 (1H, brs) WO 2008/150029 PCT/JP2008/060804 -86 Example 75 3- (2, 4-Dimethoxyphenyl) -5-fluoro-2-methyl-8-propoxy-1H-quinolin 4-one 5 Pale brown powder (ethyl acetate) Melting point 100-101 0 C IH-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.5 Hz), 1.80-1.86 (2H, m), 2.11 (3H, s), 3.65 (3H, s), 3.78 (3H, s), 4.10 (2H, t, J=6.8 Hz), 6.51-6.59 (2H, m), 10 6.80-6.94 (2H, m), 7.11-7.17 (1H, m), 10.47 (1H, brs) Example 76 5-Fluoro-3-furan-2-yl-2-methyl-8-propoxy-lH-quinolin-4-one Pale brown powder (ethyl acetate) 15 Melting point 203-204 0 C 1 H-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.5 Hz), 1.78-1.89 (2H, m), 2.47 (3H, s), 4.10 (2H, t, J=6.8 Hz), 6.52-6.54 (1H, m), 6.67-6.69 (1H, m), 6.86-6.95 (1H, m), 7.15-7.20 (1H, m), 7.67-7.68 (1H, m), 10.66 (1H, m) 20 Example 77 5-Fluoro-3-(4-methoxyphenyl)-8-propoxy-2-trifluoromethyl-1H quinolin-4-one White powder (n-hexane-ethyl acetate) 25 Melting point 170-171 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.3 Hz), 1.76-1.90 (2H, m), 3.80 (3H, s), 4.11 (2H, t, J=6.5 Hz), 6.98 (2H, d, J=8.7 Hz), 7.15-7.25 (4H, m), 10.11 (1H, brs) 30 Example 78 5-Fluoro-3-furan-2-yl-8-propoxy-2-trifluoromethyl-1H-quinolin-4 one Pale yellow powder (n-hexane-ethyl acetate) 35 Melting point 134-136 0
C
WO 2008/150029 PCT/JP2008/060804 -87 H-NMR (DMSO-d 6 ) dppm: 0.99 (3H, t, J=7.5 Hz), 1.76-1.90 (2H, m), 4.11 (2H, t, J=6.6 Hz), 6.59-6.65 (2H, m), 7.21-7.33 (2H, m), 7.81 (1H, m), 10.08 (1H, brs) 5 Example 79 3-(4-Dimethylaminophenyl)-5-fluoro-8-propoxy-2-trifluoromethyl 1H-quinolin-4-one Pale yellow powder (n-hexane-ethyl acetate) 10 Melting point 176-177 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.4 Hz), 1.76-1.91 (2H, m), 2.94 (6H, s), 4.11 (2H, t, J=6.6 Hz), 6.75 (2H, d, J=8.8 Hz), 7.03 (2H, d, J=8.8 Hz), 7.21-7.24 (2H, m), 10.00 (1H, brs) 15 Example 80 3-(4-Ethylphenyl)-5-fluoro-8-propoxy-2-trifluoromethyl-1H quinolin-4-one White powder (n-hexane-ethyl acetate) 20 Melting point 187-188 0 C 'H-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.3 Hz), 1.20 (3H, t, J=7.5 Hz), 1.77-1.91 (2H, m), 2.62-2.71 (2H, q, J=7.5 Hz), 4.12 (2H, t, J=6.6 Hz), 7.13-7.29 (6H, m), 10.23 (1H, brs) 25 Example 81 5-Fluoro-3-(4-fluorophenyl)-8-propoxy-2-trifluoromethyl-1H quinolin-4-one Brown powder (n-hexane-ethyl acetate) 30 Melting point 154-155 0 C IH-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.3 Hz), 1.81-1.89 (2H, m), 4.13 (2H, t, J=6.5 Hz), 7.10-7.31 (4H, m), 7.80-7.86 (1H, m), 8.08 (1H, s), 10.24 (1H, brs) 35 WO 2008/150029 PCT/JP2008/060804 -88 Example 82 5-Fluoro-8-propoxy-3-(4-trifluoromethoxyphenyl)-2 trifluoromethyl-1H-quinolin-4-one Pale red powder (n-hexane-ethyl acetate) 5 Melting point 143-144 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.3 Hz), 1.77-1.91 (2H, m), 4.12 (2H, t, J=6.6 Hz), 7.19-7.54 (6H, m), 10.44 (1H, brs) 10 Example 83 5-Fluoro-2-isopropyl-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4 one White powder (ethyl acetate-n-hexane) Melting point 195-197 0 C 15 'H-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.3 Hz), 1.16 (6H, d, J=7.0 Hz), 1.78-1.92 (2H, m), 2.86-2.97 (1H, m), 3.77 (3H, s), 4.13 (2H, t, J=6.4 Hz), 6.84 7.22 (6H, m), 8.98 (1H, brs) 20 Example 84 5-Fluoro-3-furan-2-yl-2-isopropyl-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate-n-hexane) Melting point 113-114 0 C 1 H-NMR (DMSO-d 6 ) dppm: 25 0.99 (3H, t, J=7.5 Hz), 1.21(6H, d, J=7.0 Hz), 1.80-1.89 (2H, m), 3.11-3.16 (1H, m), 4.12 (2H, t, J=6.4 Hz), 6.48-6.54 (2H, m), 6.90-6.98 (1H, m), 7.20-7.25 (1H, m), 7.69-7.70 (1H, m), 9.29 (lH, brs) 30 Example 85 5-Fluoro-8-propoxy-3-thiophen-2-yl-2-trifluoromethyl-1H-quinolin 4-one Pale yellow powder (ethyl acetate-n-hexane) Melting point 149-150 0 C 35 1 H-NMR (DMSO-d 6 ) dppm: WO 2008/150029 PCT/JP2008/060804 -89 1.00 (3H, t, J=7.4 Hz), 1.76-1.90 (2H, m), 4.11 (2H, t, 6.4 Hz), 7.10-7.30 (4H, m), 7.72-7.75 (1H, m), 10.52 (1H, brs) Example 86 5 5-Fluoro-8-furan-2-yl-3-(4-methoxyphenyl)-1H-quinolin-4-one 8-bromo-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin-4-one (150 mg, 0.43 mmol), 2-furan boronic acid (145 mg, 1.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane complex (PdCl 2 (DPPF)) (35 mg, 0.04 mmol) and a 2N 10 sodium carbonate aqueous solution (1 ml) were added to 1,2 dimethoxyethane (3 ml), and the mixture was heated at 180 0 C for 10 minutes (microwave reactor). After the reaction mixture was cooled to room temperature, dichloromethane was added, and then filtration with Celite was carried out. The filtrate was 15 extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane). The purified product was concentrated under reduced pressure, and 20 the residue was recrystallized from n-hexane-ethyl acetate to thereby obtain 100 mg of powdery slightly orange 5-fluoro-8 furan-2-yl-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 70%). Melting point 209-211 0 C 1 H-NMR (DMSO-d 6 ) dppm: 25 3.79 (3H, s), 6.74-6.77 (1H, m), 6.96-7.00 (3H, m), 7.07-7.15 (1H, m), 7.55-7.59 (2H, m), 7.81-7.93 (3H, m), 11.00 (1H, brs) The compounds of the following Examples 87 and 88 were prepared in the same manner as the above Example 86, using 30 corresponding starting materials. Example 87 5-Fluoro-3-(4-methoxyphenyl)-8-thiophen-3-yl-1H-quinolin-4-one Pale yellow powder (ethyl acetate) 35 Melting point 183-184 0
C
WO 2008/150029 PCT/JP2008/060804 -90 H-NMR (DMSO-d 6 ) dppm: 3.76 (3H, s), 6.93-7.09 (3H, m), 7.30-7.32 (1H, m), 7.49-7.54 (3H, m), 7.76-7.80 (3H, m), 10.64 (1H, brs) 5 Example 88 8-Benzo[bIthiophen-2-yl-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin 4-one Pale yellow powder (ethyl acetate) Melting point 276-277 0 C 10 IH-NMR (DMSO-d 6 ) dppm: 3.76 (3H, s), 6.84-6.92 (3H, m), 7.30-7.40 (2H, m), 7.62-7.66 (2H, m), 7.84-7.99 (5H, m), 11.03 (iH, brs) Example 89 15 4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid Methyl 4-(5-fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin 3-yl)benzoate (330 mg, 0.93 mmol) was suspended in a mixed solvent of ethanol (3 ml) and THF (3 ml). A 1.24N lithium hydroxide aqueous solution (2 ml) was added, and the mixture was 20 stirred at room temperature for 3 hours. Water was added to the reaction mixture, and then the resulting mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to thereby obtain 300 mg of powdery white 4-(5 25 fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)benzoic acid (yield: 95%). IH-NMR (DMSO-d 6 ) dppm: 1.01-1.07(3H, t, J=7.3 Hz), 1.80-1.91(2H, m), 4.09-4.14(2H, t, J=6.4 Hz), 6.85-7.24(3H, m), 7.75-7.78(2H, m), 7.92-7.95(2H, m), 30 11.51(lH, brs), 12.84(1H, brs) Example 90 5-Fluoro-3-[4-(morpholine-4-carbonyl)phenyl]-8-propoxy-1H quinolin-4-one 35 4-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3- WO 2008/150029 PCT/JP2008/060804 -91 yl)benzoic acid (260 mg, 0.76 mmol), morpholine (99.5 mg, 1.14 mmol), WSC (189 mg, 0.99 mmol) and HOBT (151 mg, 0.99 mmol) were added to DMF (10 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated 5 under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane : methanol = 30 : 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 80 mg of powdery white 5-fluoro-3-[4 10 (morpholine-4-carbonyl)phenyl]-8-propoxy-1H-quinolin-4-one (yield: 26%). Melting point 234-236 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.4 Hz), 1.80-1.89 (2H, m), 3.40-3.60 (8H, m), 15 4.09 (2H, t, J=6.5 Hz), 6.89-6.98 (1H, m), 7.16-7.21 (1H, m), 7.41 (2H, d, J=8.3 Hz), 7.69 (2H, d, J=8.3 Hz), 7.91 (1H, s), 11.41 (1H, brs) Example 91 20 5-Fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one Sodium hydride (60% in oil, 76 mg, 1.9 mmol) was added to a DMF solution (10 ml) of 5-fluoro-3-(4-methoxyphenyl)-8 propoxy-1H-quinolin-4-one (400 mg, 1.22 mmol). The mixture was stirred at room temperature for 15 minutes. Methyl iodide (225 mg, 25 1.6 mmol) was added thereto, and then the resulting mixture was stirred at room temperature for 19 hours. Water and ethyl acetate were added to the reaction mixture to separate the mixture into two layers. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced 30 pressure. The residue was then purified by silica gel column chromatography (n-hexane : ethyl acetate = 1 : 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 365 mg of powdery pale yellow 5-fluoro-3-(4-methoxyphenyl)-1-methyl-8 35 propoxy-1H-quinolin-4-one (yield: 72%).
WO 2008/150029 PCT/JP2008/060804 -92 Melting point 147-148'C 1 H-NMR (DMSO-d,) dppm: 0.98 (3H, t, J=7.5 Hz), 1.77 (2H, m), 3.76 (3H, s), 3.98 (2H, t, J=6.4 Hz), 4.08 (3H, s), 6.91-7.01 (3H, m), 7.19-7.24 (lH, m), 5 7.57-7.61 (2H, m), 7.96 (lH, s) The compounds of the following Examples 92 to 94 were prepared in the same manner as the above Example 91, using corresponding starting materials. 10 Example 92 1-Ethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one White powder (ethyl acetate) Melting point 123-125 0 C 15 IH-NMR (DMSO-d 6 ) dppm: 1.00 (3H, t, J=7.3 Hz), 1.29 (3H, t, J=6.8 Hz), 1.79-1.88 (2H, m), 3.76 (3H, s), 4.03 (2H, t, J=6.5 Hz), 4.52 (2H, q, J=6.8 Hz), 6.91-7.02 (3H, m), 7.22-7.27 (1H, m), 7.60 (2H, d, J=8.7 Hz), 8.00 (lH, s) 20 Example 93 1- (2-Ethoxyethyl) -5-fluoro-3- (4-methoxyphenyl) -8-propoxy-1H quinolin-4-one White powder (ethyl acetate) 25 Melting point 108-109 0 C 'H-NMR (DMSO-d 6 ) dppm: 0.96-1.09 (6H, m), 1.77-1.89 (2H, m), 3.65 (2H, t, J=5.0 Hz), 3.78 (3H, s), 4.02 (2H, t, J=6.8 Hz), 4.72 (2H, t, J=5.0 Hz), 6.94-7.04 (3H, m), 7.23-7.29 (1H, m), 7.57 (2H, d, J=8.7 Hz), 30 7.93 (lH, s) Example 94 1-Cyclopropylmethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H quinolin-4-one 35 Pale yellow powder (n-hexane) WO 2008/150029 PCT/JP2008/060804 -93 Melting point 60-62 0 C 'H-NMR (DMSO-d,) dppm: 0.36-0.51 (4H, m), 1.07(3H, t, J=7.4 Hz), 1.26-1.30 (lH, m), 1.86-1.94 (2H, m), 4.09 (2H, t, J=6.5 Hz), 6.96-7.08 (3H, m), 5 7.28-7.33 (lH, m), 7.61-7.66 (2H, m), 8.05 (1H, s) Example 95 5-Fluoro-3- (4-hydroxyphenyl) -8-propoxy-1H-quinolin-4-one A dichloromethane solution (5 ml) of 5-fluoro-3-(4 10 methoxyphenyl)-8-propoxy-1H-quinolin-4-one (249 mg, 0.76 mmol) was cooled to -10 0 C in a methanol-ice bath. A IN boron tribromide (4.08 ml) was added thereto, and the mixture was stirred at room temperature for 6 hours. Ice water and dichloromethane were added to the reaction mixture, and the resultant insoluble matter was 15 collected by filtration. The filtrate was separated and the organic layer was concentrated under reduced pressure. The residue and the substance remaining on the filter were mixed, and the mixture was purified by silica gel column chromatography (dichloromethane : methanol = 60 : 1 - 25 : 1). The purified 20 product was concentrated under reduced pressure. Ethyl acetate was added to crystallize the residue. The crystals were collected by filtration, washed with ethyl acetate, and then dried to thereby obtain 220 mg of powdery pale yellow 5-fluoro-3-(4 hydroxyphenyl) -8-propoxy-1H -quinolin-4-one (yield: 92%). 25 Melting point 271-272 0 C IH-NMR (DMSO-d 6 ) dppm: 1.03 (3H, t, J=7.3 Hz), 1.78-1.87 (2H, m), 4.08 (2H, t, J=6.4 Hz), 6.77 (2H, d, J=8.6 Hz), 6.87 (1H, dd, J=8.8 Hz, J=12.lHz), 7.12 (1H, dd, J=3.9 Hz, J=8.8 Hz), 7.41 (2H, d, J=8.6 Hz), 7.77 (lH, 30 s), 9.43 (lH, brs), 11.20 (lH, brs) Example 96 5-Fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinolin-4-one 5-Fluoro-8-methoxy-3-(4-methoxyphenyl)-1H-quinolin-4 35 one (1.0 g, 3.34 mmol) was suspended in dichloromethane (40 ml), WO 2008/150029 PCT/JP2008/060804 -94 and the suspension was cooled to -10 0 C in a methanol-ice bath. A IN boron tribromide (17 ml) was added thereto, and the resulting mixture was stirred at room temperature for 15 hours. Ice water and dichloromethane were added to the reaction mixture, and the 5 resultant insoluble matter was collected by filtration. The substance remaining on the filter was washed with water, dried and purified by silica gel column chromatography (dichloromethane : methanol = 20 : 1 -> 8 : 1 --> ethyl acetate methanol = 4 : 1). The purified product was concentrated under 10 reduced pressure and ethyl acetate was then added to crystallize the residue. The crystals were collected by filtration, washed with ethyl acetate, and dried to thereby obtain 360 mg of powdery pale gray 5-fluoro-8-hydroxy-3-(4-hydroxyphenyl)-1H-quinolin-4 one (yield: 40%). 15 Melting point 303-305 0 C (decomposition) 1 H-NMR (DMSO-d 6 ) dppm: 6.74-6.82 (3H, m), 6.94 (lH, dd, J=4.1 Hz, J= 8.5 Hz), 7.41 (2H, d, J=8.3 Hz), 7.74 (lH, s), 9.46 (1H, brs), 10.70 (1H, brs), 11.32 (lH, brs) 20 Example 97 5-Fluoro-3-(4-hydroxy-2-methoxyphenyl)-8-propoxy-1H-quinolin-4 one Aluminum chloride (108 mg, 0.81 mmol) was added to a 25 dichloromethane solution (5 ml) of 5-fluoro-3-(4-isopropoxy-2 methoxyphenyl)-8-propoxy-1H-quinolin-4-one (120 mg, 0.31 mmol). The mixture was stirred at room temperature for 1 hour. Water and dichloromethane were added to the reaction mixture, and separated. The organic layer was then washed with water. The washed organic 30 layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane methanol = 10 : 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl 35 acetate to thereby obtain 100 mg of powdery white 5-fluoro-3-(4- WO 2008/150029 PCT/JP2008/060804 -95 hydroxy-2-methoxyphenyl) -8 -propoxy- 1H-quinolin- 4 -one (yield: 90%). Melting point 251-253 0 C IH-NMR (DMSO-d 6 ) dppm: 1.01-1.07(3H, t, J=7.4 Hz), 1.77-1.88(2H, m), 3.63(3H, s), 4.07 5 4.12(2H, t, J=6.6 Hz), 6.33-6.43(2H, m), 6.84-6.90(1H, m), 7.02 7.11(2H, m), 7.61-7.64(1H, m), 9.39(lH, s), 11.07(1H, brs) The compound of the following Example 98 was prepared in the same manner as the above Example 97, using corresponding 10 starting materials. Example 98 5-Fluoro-3-(2-hydroxy-4-methoxyphenyl)-8-propoxy-1H-quinolin-4 one 15 White powder (ethyl acetate) Melting point 208-209 0 C IH-NMR (DMSO-d 6 ) dppm: 1.02 (3H, t, J=7.5 Hz), 1.81-1.90 (2H, m), 3.73 (3H, s), 4.11 (2H, t, J=6.5 Hz), 6.43-6.51 (2H, m), 6.98-7.06 (1H, m), 7.16-7.25 (2H, 20 m), 7.95 (1H, s), 10.23 (1H, s), 11.93 (1H, brs) Example 99 5-Fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinolin-4-one 2N Hydrochloric acid (6.0 ml) was added to an ethanol 25 solution (18 ml) of 5-fluoro-8-methoxymethoxy-3-(4 methoxyphenyl)-lH-quinolin-4-one (350 mg, 1.06 mmol). The mixture was stirred at 55 0 C for 1 hour. The stirred mixture was cooled to room temperature, and 1N sodium hydrate (11.6 ml) was added thereto to obtain a pH of 3 to 4. The mixture in which pH was 30 adjusted was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane : methanol = 50 :1 -+ 20 : 1). The purified product was concentrated under reduced pressure, and the residue was crystallized from ethanol, collected by filtration, washed 35 with ethanol, and dried to thereby obtain 165 mg of powdery pale WO 2008/150029 PCT/JP2008/060804 -96 dark brown 5-fluoro-8-hydroxy-3-(4-methoxyphenyl)-1H-quinolin-4 one (yield: 54%). Melting point 270-272 0 C 1 H-NMR (DMSO-d 6 ) dppm: 5 3.75 (3H, s), 6.79 (1H, dd, J=8.5 Hz, J= 12.1Hz), 6.90-6.97 (3H, m), 7.53 (2H, d, J=8.6 Hz), 7.77 (1H, s), 10.60 (1H, brs), 11.40 (1H, brs) Example 100 10 5-Fluoro-3-(2-hydroxymethylthiophen-3-yl)-8-propoxy-1H-quinolin 4-one 3- (5-Fluoro-4-oxo-8-propoxy-1, 4-dihydroquinolin-3-yl) thiophene-2-carbaldehyde (120 mg, 0.39 mmol) was suspended in ethanol (5 ml), and sodium borohydride (19.24 mg) was added to 15 the suspension. The resulting mixture was stirred at room temperature for 1 hour. Dichloromethane was added to the reaction mixture, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified by silica gel column 20 chromatography (dichloromethane : methanol = 30 : 1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 110 mg of powdery white 5-fluoro-3-(2-hydroxymethylthiophen-3 yl)-8-propoxy-1H-quinolin-4-one (yield: 82%). 25 Melting point 181-184 0 C H-NNR (DMSO-d 6 ) dppm: 1.01 (3H, t, J=7.3 Hz), 1.79-1.88 (2H, m), 4.07 (2H, t, J=6.4 Hz), 4.47 (2H, d, J=5.4 Hz), 5.48 (1H, t, J=5.4 Hz), 6.87-6.96 (1H, m), 7.11-7.19 (2H, m), 7.39-7.40 (1H, m), 7.88 (1H, s), 11.36 (1H, 30 brs) Example 101 5-Fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4 one 35 8-(3-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H- WO 2008/150029 PCT/JP2008/060804 -97 quinolin-4-one (1.95 g, 4.49 mmol) and a 10% palladium carbon (720 mg) were added to ethanol (50 ml). The mixture was stirred at 50 0 C for 7.5 hours under a hydrogen atmosphere (1 atmosphere) and subjected to a catalytic reduction. The reaction mixture was 5 cooled to room temperature, and filtration with Celite was conducted to remove the solvent. The filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane : methanol = 80 :1 -+ 20 : 1). The purified product was concentrated under reduced 10 pressure, and the residue was concentrated to dryness to thereby obtain 820 mg of pale dark brown amorphous solid 5-fluoro-8-(3 hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 53%). 'H-NMR (DMSO-ds) dppm: 15 1.92-2.02 (2H, m), 3.65 (2H, t, J=5.9 Hz), 4.20 (2H, t, J=6.2Hz), 4.59 (lH, brs), 6.84-6.95 (3H, m), 7.14 (1H, dd, J=3.9 Hz, J= 8.8 Hz), 7.55 (2H, d, J=8.7 Hz), 7.80 (1H, s), 11.27 (lH, brs) The compound of the following Example 102 was prepared 20 in the same manner as the above Example 101, using corresponding starting materials. Example 102 5-Fluoro-8- (2-hydroxypropoxy) -3- (4-methoxyphenyl) -1H-quinolin-4 25 one White powder (ethyl acetate) Melting point 216-218 0 C IH-NMR (DMSO-d 6 ) dppm: 1.19 (3H, d, J=6.2Hz), 3.76 (3H, s), 3.82-4.12 (3H, m), 5.25 (1H, 30 brs), 6.84-6.96 (3H, m), 7.12 (1H, dd, J=3.9 Hz, J= 8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.86 (1H, s), 11.20 (1H, brs) The compounds of the following Examples 103 and 104 were prepared in the same manner as the above Example 1, using 35 corresponding starting materials.
WO 2008/150029 PCT/JP2008/060804 -98 Example 103 5-Chloro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one Pale brown powder (ethyl acetate) 5 Melting point 194-196 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.03 (3H, t, J=7.3 Hz), 1.80-1.87 (2H, m), 3.76 (3H, s), 4.11 (2H, t, J=6.4 Hz), 6.93 (2H, d, J=8.6 Hz), 7.12 (1H, d, J=8.5 Hz), 7.17 (1H, d, J=8.5 Hz), 7.54 (2H, d, J=8.6 Hz), 7.80 (1H, s), 10 11.23 (1H, brs) Example 104 5-Bromo-8-cyclopentyloxy-3- (4-methoxyphenyl) -1H-quinolin-4-one Pale brown powder (ethanol) 15 Melting point 213-215 0 C 1 H-NMR (DMSO-d 6 ) dppm: 1.59-1.70 (2H, m), 1.71-2.00 (6H, m), 3.75 (3H, s), 4.97-5.00 (1H, m), 6.94 (2H, d, J=8.7Hz), 7.04 (1H, d, J=8.5 Hz), 7.40 (1H, d, J=8.4 Hz), 7.53 (2H, d, J=8.7 Hz), 7.81 (1H, s), 11.20 (1H, brs) 20 Pharmacological Test 1 Evaluation of improvement of mitochondrial dysfunction using human neuroblastoma cell lines SH-SY5Y treated with 1-methyl-4 phenylpyridinium (MPP*) 25 In human neuroblastoma cell lines SH-SY5Y in which mitochondrial activity was injured by MPP' treatment (Bollimuntha S. et al., J Biol Chem, 280, 2132-2140 (2005) and Shang T. et al., J Biol Chem, 280, 34644-34653 (2005)), improvement of the mitochondrial dysfunction was evaluated on the basis of the 30 measurement value of the mitochondrial oxidation reduction activity using Alamar Blue fluorescent dye after the compound addition (Nakai M. et al, Exp Neurol, 179, 103-110 (2003)). The human neuroblastoma cell lines SH-SY5Y were cultured in Dulbecco's Modified Eagle's Medium containing 10% 35 fetal bovine serum (DMEM containing 50 units/ml penicillin and 50 WO 2008/150029 PCT/JP2008/060804 -99 tg/ml streptomycin as antibiotics) at 37'C in the presence of 5% carbon dioxide. Cells were scattered on a poly-D-lysine-coated 96-well black plate at a concentration of 3-6 x 104 cells/cm 2 (medium amount: 100 L/well), and cultured in the above medium 5 for two days. Further, the medium was changed to a DMEM containing a 1% N2 supplement (N2-DMEM) or to a medium (100 pl/well) in which 1.5 mM MPP* was dissolved. The cells were cultured therein for 39 to 48 hours, and then subjected to a mitochondrial oxidation reduction activity measurement system. A 10 sample compound that had been previously dissolved in dimethyl sulfoxide (DMSO) was diluted with N2-DMEM, and added in a volume of 10 pl/well 24 hours before the activity measurement (final compound concentration: 0.01 to 1 Rg/ml). After removal of the medium by suction, a balanced salt 15 solution containing 10% Alamar Blue (154 mM sodium chloride, 5.6 mM potassium chloride, 2.3 mM calcium chloride, 1.0 mM magnesium chloride, 3.6 mM sodium bicarbonate, 5 mM glucose, 5 mM HEPES, pH 7.2) was added in a volume of 100 R1/well, and reacted in an incubator at 37 0 C for 1 hour. The fluorescent intensity was 20 detected using a fluorescence detector (a product of Hamamatsu Photonics K.K., excitation wavelength 530 nm, measurement wavelength 580 nm) to thereby measure the mitochondrial oxidation reduction activity. The fluorescent intensity of the well of the cells 25 cultured in a medium containing MPP* and in each of the sample compounds was relatively evaluated based on a 100% fluorescent intensity of the well of the cells cultured in a medium containing DMSO alone (final concentration: 0.1%). When the MPP* induced cell groups exhibited higher florescent intensity than 30 the cell groups cultured in DMSO alone, the test compound was judged to have the improved activity of the mitochondrial dysfunction.
WO 2008/150029 PCT/JP2008/060804 -100 Table 1 Evaluation of improvement of mitochondrial dyfunction using human neuroblastoma cell lines SH-SY5Y treated with 1-methyl-4 phenylpyridinium (MPP*) 5 Test Compound Fluorescence Intensity (%) Concentration (p1g/ml) 0 0.01 0.03 0.1 0.3 1 Compound of 50 51 62 70 66 64 Example 1 Compound of 51 54 63 70 78 74 Example 3 Compound of 47 56 61 70 72 59 Example 4 Compound of 53 59 71 85 88 83 Example 6 Compound of 46 52 59 63 74 57 Example 21 Compound of 54 60 70 82 78 84 Example 24 Compound of 41 46 56 66 50 24 Example 25 Compound of 46 50 54 69 64 56 Example 30 Compound of 38 45 45 57 59 48 Example 31 Compound of 60 69 74 77 78 87 Example 34 Compound of 63 75 88 99 95 65 Example 35 Compound of 59 63 65 74 71 91 Example 36 Compound of 57 64 73 78 70 61 Example 37 Compound of 54 66 67 86 81 78 Example 38 Compound of 53 60 64 76 70 72 Example 40 Compound of 49 51 58 71 73 82 Example 47 Compound of 48 53 56 67 60 67 Example 53 Compound of 50 53 56 67 66 54 Example 59 Compound of 61 70 65 85 80 86 Example 61 WO 2008/150029 PCT/JP2008/060804 -101 Table 1 (continued) Test Compound Fluorescence Intensity (%) Concentration (pg/ml) 0 0.01 0.03 0.1 0.3 1 Compound of 55 66 62 79 84 80 Example 62 Compound of 56 58 65 74 75 85 Example 63 Compound of 56 55 65 74 72 77 Example 64 Compound of 57 66 72 83 77 60 Example 66 Compound of 53 56 57 67 71 63 Example 70 Compound of 50 56 61 73 78 72 Example 71 Compound of 46 52 59 68 61 39 Example 86 Compound of 58 63 66 79 63 51 Example 87 Compound of 55 65 69 81 82 83 Example 91 Compound of 55 63 75 77 69 55 Example 92 Compound of 58 66 79 86 80 69 Example 93 Compound of 51 56 67 69 59 41 Example 94 Compound of 53 56 56 71 73 84 Example 100 Pharmacological Test 2 5 Evaluation of dopaminergic neuronal protective activity using C57BL/6 mouse treated with 1-methyl-4-phenyl 1,2,3,6-tetrahydro pyridine (MPTP) Using a mouse having MPTP-injured dopaminergic neurons (Chan P. et al., J Neurochem, 57,348-351 (1991)), the dopamine 10 neuroprotective activity was evaluated based on dopamine contents and protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) (i.e., dopaminergic neuronal marker proteins) in the brain corpus striatum region after the compound administration (Mori A. et al., Neurosci Res, 51, 265-274(2005)). 15 A male C57BL/6 mouse (provided by Japan Charles River WO 2008/150029 PCT/JP2008/060804 -102 Inc., 10 to 12 weeks) was used as a test animal. MPTP was dissolved in a physiological salt solution so that the concentration became 4 mg/ml, and then administered to the mouse subcutaneously in a volume of 10 ml/kg. The test compound was 5 suspended in a 5% gum arabic/physiological salt solution (w/v) so that a compound having a concentration of 1 mg/ml could be obtained. Each of the test compounds or solvents thereof was orally administered to the mouse after 30 minutes, 24 hours, and 48 hours of the MPTP administration. The mouse was decapitated 10 after 72 hours of the MPTP administration, the brain was removed, and each side of the striatum was dissected. The left striatum was used as a sample to detect the protein level by Western blot analysis. Each tissue was homogenized in a HEPES buffer sucrose solution (0.32 M sucrose, 4 15 ptg/ml pepstatin, 5 pg/ml aprotinin, 20 pg/ml trypsin inhibitor, 4 pg/ml leupeptin, 0.2 mM phenylmethanesulfonyl fluoride, 2 mM ethylenediaminetetraacetic acid (EDTA), 2 mM ethylene glycol bis (P aminoethyl ether) tetraacetic acid, 20 mM HEPES, pH 7.2), and assayed for protein using a bicinchoninic acid kit for protein 20 assay (provided by Pierce Corporation). Each homogenized sample, having an equal amount of protein which had been dissolved in a Laemmli sample buffer solution, was subjected to electrophoresis through sodium dodecyl sulfurate polyacrylamide gels. The protein separated by electrophoresis was electrically transferred to 25 polyvinylidene fluoride membranes. The membranes were reacted with specific primary antibody for TH, DAT, and housekeeping proteins, i.e., the al subunit of Na*/K*-ATPase and actin (Na*/K* ATPase, a product of UpState Biotechnology Inc.; others are products of Chemi-Con Corporation). Subsequently, a horseradish 30 peroxidase-labeled secondary antibody (a product of Amersham K.K.) for each primary antibody was fixed, and the chemiluminescence associated with enzyme activity of peroxidase was detected using X-ray film. The density of the protein band on the film was analyzed using a densitometer (a product of Bio-rad 35 Laboratories Inc.) to obtain the TH value relative to Na*/K*- WO 2008/150029 PCT/JP2008/060804 -103 ATPase and the DAT value relative to actin. The right striatum, the tissue weight of which was measured immediately after dissection, was used as an analysis sample for determining the dopamine content. Each tissue was 5 homogenized in a 0.1 N perchloric acid solution containing isoproterenol as an internal standard substance of the measurement, using an ultrasonic homogenizer while being cooled with ice. The supernatant obtained from 20,000 g of homogenate that had been centrifuged at 4 0 C for 15 minutes was subjected to a 10 high performance liquid chromatography with a reversed phase column (a product of Eicom Corporation). A mobile phase 15% methanol 0.1 M citric acid/0.1 M sodium acetate buffer solution (containing 190 mg/l 1-sodium octane sulfonate, 5 mg/l EDTA, pH 3.5) was flowed at a rate of 0.5 ml/min, and the dopamine peak of 15 each sample was detected using an electrochemical detector (applied voltage +750 my vs. Ag/AgCl, a product of Eicom Corporation). With reference to the identified dopamine peak, the dopamine content per tissue weight was calculated in each sample using analysis software (a product of Gilson Inc.). 20 In both analyses, the value of the sample derived from the MPTP-induced mice in which only the test compound or the solvent was administered was expressed relative to the value of the sample derived from the mice without MPTP treatment (100%). Values were analyzed statistically using a nonclinical 25 statistical analysis system. Values of significance probability < 0.05 were defined as statistically significant. In the MPTP induced mice, when the test drug group showed an increase in protein level compared to the solvent group, and a significant difference was observed between these groups at t-assay, the test 30 drug was judged to have dopamine neuroprotective activity.

Claims (6)

1. A quinolone Compound represented by General Formula (1) R4 O R5 R3 R6 N R2 R7 R1 5 or a salt thereof, wherein R, represents a hydrogen atom, a lower alkyl group, a cyclo C 3 . 8 alkyl lower alkyl group, or a lower alkoxy lower alkyl group; 10 R 2 represents a hydrogen atom, a lower alkyl group, or a halogen-substituted lower alkyl group; R 3 represents a phenyl group, a furyl group, a thienyl group, or a pyridyl group, each of the groups optionally being substituted with one or more groups selected from the group 15 consisting of the following (1) to (16) on the aromatic or heterocyclic ring represented by the above R 3 : (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups, 20 (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, 25 (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted with one or more lower alkyl groups, WO 2008/150029 PCT/JP2008/060804 -105 (12) carbamoyl groups optionally substituted with one or more lower alkyl groups, (13) cyclo C 3 - 8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, 5 (15) morpholinyl carbonyl groups, and (16) a carboxyl group; R 4 represents a halogen atom; R 5 represents a hydrogen atom or a halogen atom; R 6 represents a hydrogen atom; and 10 R 7 represents any one of groups (1) to (15) below; (1) a hydroxy group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, 15 (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted with one or more members selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl groups, and cyclo C 3 - 8 alkyl groups, 20 (8) an amino lower alkoxy group optionally substituted on the amino group with one or more members selected from the group consisting of lower alkyl groups, lower alkanoyl groups, lower alkyl sulfonyl groups, and carbamoyl groups optionally substituted with one or more lower alkyl groups, 25 (9) a cyclo C 3 -a alkyloxy group, (10) a cyclo C 3 . 8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group selected from the group consisting of 30 morpholinyl groups, pyrrolidinyl groups, furyl groups, thienyl groups, and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group, and (15) a pyrrolidinyl carbonyl group. 35 2. A quinolone compound of General Formula (1) or a salt WO 2008/150029 PCT/JP2008/060804 -106 thereof according to claim 1, wherein R. represents a hydrogen atom or a lower alkyl group; R 2 represents a hydrogen atom or a lower alkyl group; 5 R 3 represents a phenyl group or a pyridyl group, each of the groups optionally being substituted with one or two groups selected from the group consisting of the following (1), (2), (6), and (8) on the aromatic or heterocyclic ring represented by the above R 3 : 10 (1) lower alkyl groups, (2) lower alkoxy groups, (6) a hydroxy group, and (8) halogen atoms; R 4 represents a halogen atom; 15 R 5 represents a hydrogen atom; R 6 represents a hydrogen atom; and R 7 represents any one of groups (3), (4), and (7) below: (3) a lower alkoxy group, 20 (4) a halogen-substituted lower alkoxy group, and (7) an amino group optionally substituted with one or two lower, alkyl groups
3. A quinolone compound of General Formula (1) or a salt 25 thereof according to claim 2 selected from the group consisting of:
5-fluoro-3-(4-methoxyphenyl)-2-methyl-8-propoxy-1H-quinolin-4-one, 5-fluoro-3-(4-methoxyphenyl)-1-methyl-8-propoxy-1H-quinolin-4-one, 3- (2, 4-dimethoxyphenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one, 30 5-fluoro-8-isopropoxy-3-(4-methoxyphenyl)-1H-quinolin-4-one, 3- (2, 4-dichlorophenyl) -5-fluoro-8-propoxy-1H-quinolin-4-one,
8-ethoxy-5-fluoro-3- (4-methoxyphenyl) -1H-quinolin-4-one, 5-fluoro-3- (4-methoxy-2-methylphenyl) -8-propoxy-lH-quinolin-4-one, 5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one, 35 5-fluoro-3-(2-fluoro-4-methoxyphenyl)-8-propoxy-lH-quinolin-4-one, 107 5-fluoro-3- (4-hydroxyphenyl) -8-propoxy-lH-quinolin-4-one, 8-cyclopropylmethoxy-5-fluoro-3- (4-methoxyphenyl) -lH-quinolin 4-one, 5-fluoro-8-propoxy-3-pyridin-4-yl-lH-quinolin-4-one, 5 5-fluoro-3- (4-methoxyphenyl) -8- (N-methyl-N-propylamino) -lH quinolin-4-one, and 5-fluoro-3- (4-methoxyphenyl) -8- (4,4,4-trifluorobutoxy) -1H quinolin-4-one. 4. A pharmaceutical composition comprising a .0 quinolone compound of General Formula (1) or a salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier. 5. A prophylactic and/or therapeutic agent for neurodegenerative diseases, diseases induced by neurological .5 dysfunction, or diseases induced by deterioration of mitochondrion function, comprising as an active ingredient a quinolone compound of General Formula (1) or a salt thereof according to claim 1. 6. A prophylactic and/or therapeutic agent .0 according to claim 5, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, 25 corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism, dystonia musculorum 30 deformance, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar WO 2008/150029 PCT/JP2008/060804 -108 atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler Scheinker disease, Friedreich's Ataxia, Roussy-Levy syndrome, 5 May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraparesis, 10 syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiffman syndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy selected from the group 15 consisting of cerebral infarction and cerebral hemorrhage. 7. A prophylactic and/or therapeutic agent according to claim 5, wherein the disease induced by neurological dysfunction is selected from the group consisting of spinal cord 20 injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage, and demyelinating diseases selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing panencephalitis, chronic 25 inflammatory demyelinating polyneuropathy and Guillain-Barre syndrome. 8. A prophylactic and/or therapeutic agent according to claim 5, wherein the disease induced by deterioration of 30 mitochondrion function is selected from the group consisting of Pearson's syndrome, diabetes, deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, 35 aminoglycoside-induced hearing loss, complex III deficiency due WO 2008/150029 PCT/JP2008/060804 -109 to inherited variants of cytochrome b, multiple symmetrical lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve 5 atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency, mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic-progressive-external-ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, 10 schizophrenia, major depression disorder, bipolar I disorder, bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression/chronic depression, double depression and 15 acute renal failure.
9. Use of a quinolone compound of General Formula (1) or a salt thereof according to claim 1 as a drug. 20 10. A method for treating or preventing neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrion function, comprising administering a quinolone compound of General Formula (1) or a salt thereof according to 25 claim 1 to a human or an animal.
11. A process for producing a quinolone compound of General Formula (1) WO 2008/150029 PCT/JP2008/060804 -110 R4O R5 R3 R6 N R2 R7 R1 or a salt thereof, wherein RI, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each defined above in claim 1, comprising reacting a compound 5 represented by General Formula (4) (4) R7 R, wherein R 1 , R 4 , R 5 , R 6 and R 7 are each defined above in claim 1, with a compound represented by General Formula (5) 10 HO R" Ra (5) 0 wherein R 2 and R 3 are each defined above in claim 1, and R 8 represents a lower alkoxy group, thereby giving an intermediate compound represented by General Formula (6) 15 111 R4 0 R Re R 3 R RS N R2 R7 R, (6) wherein R 1 , R2, R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each defined above; and subjecting the resulting compound to a cyclization reaction. 5 12. A compound according to claim 1, substantially as hereinbefore described with reference to any one of the examples, excluding the reference examples.
AU2008260867A 2007-06-06 2008-06-06 Quinolone compound and pharmaceutical composition Ceased AU2008260867B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2007-150819 2007-06-06
JP2007150819 2007-06-06
PCT/JP2008/060804 WO2008150029A1 (en) 2007-06-06 2008-06-06 Quinolone compound and pharmaceutical composition

Publications (2)

Publication Number Publication Date
AU2008260867A1 AU2008260867A1 (en) 2008-12-11
AU2008260867B2 true AU2008260867B2 (en) 2011-03-17

Family

ID=39730840

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2008260867A Ceased AU2008260867B2 (en) 2007-06-06 2008-06-06 Quinolone compound and pharmaceutical composition

Country Status (28)

Country Link
US (5) US8269011B2 (en)
EP (1) EP2152699B1 (en)
JP (1) JP5063708B2 (en)
KR (4) KR101536883B1 (en)
CN (1) CN101679392B (en)
AR (1) AR066872A1 (en)
AT (1) ATE499368T1 (en)
AU (1) AU2008260867B2 (en)
BR (1) BRPI0812234A2 (en)
CA (1) CA2688448C (en)
CO (1) CO6270258A2 (en)
CY (1) CY1111936T1 (en)
DE (1) DE602008005137D1 (en)
DK (1) DK2152699T3 (en)
ES (1) ES2360572T3 (en)
HK (1) HK1139153A1 (en)
HR (1) HRP20110151T1 (en)
IL (1) IL201894A (en)
MX (1) MX2009013239A (en)
MY (1) MY148098A (en)
NZ (1) NZ580919A (en)
PL (1) PL2152699T3 (en)
PT (1) PT2152699E (en)
RU (1) RU2490259C2 (en)
SI (1) SI2152699T1 (en)
TW (1) TWI366565B (en)
UA (1) UA98789C2 (en)
WO (1) WO2008150029A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI366565B (en) * 2007-06-06 2012-06-21 Otsuka Pharma Co Ltd Quinolone compound and pharmaceutical composition
CA2745015A1 (en) * 2008-12-05 2010-06-10 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical agent comprising quinolone compound
WO2010065905A2 (en) * 2008-12-05 2010-06-10 Oregon Health & Science University Compounds having antiparasitic or anti-infectious activity
TWI472525B (en) 2008-12-05 2015-02-11 Otsuka Pharma Co Ltd Quinolone compound and pharmaceutical composition
US8598354B2 (en) * 2008-12-05 2013-12-03 University Of South Florida Compounds having antiparasitic or anti-infectious activity
US20120276165A1 (en) * 2009-12-09 2012-11-01 Barlaa B.V. Micro-colloidal silicic acid/boric acid composition and a method of preparing a bioenhancing solution and powder
JP5769504B2 (en) * 2010-06-04 2015-08-26 大塚製薬株式会社 Medicine
WO2012066330A1 (en) 2010-11-17 2012-05-24 Heptares Therapeutics Limited Compounds useful as a2a receptor inhibitors
WO2017112678A1 (en) 2015-12-21 2017-06-29 Rima Mcleod Compounds and methods for treating, detecting, and identifying compounds to treat apicomplexan parasitic diseases

Family Cites Families (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3416695A1 (en) 1984-05-05 1985-11-07 Bayer Ag, 5090 Leverkusen AMIDINOHYDRAZONE OF TETRALINE, CHROMONE, THIOCHROMONE AND TRETRAHYDROQUINOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS
EP0343574B1 (en) * 1988-05-24 1994-07-27 Kirin Beer Kabushiki Kaisha 4(1H)-quinolone derivatives
GB9022785D0 (en) 1990-10-19 1990-12-05 Merck Sharp & Dohme Therapeutic agents
GB9026389D0 (en) 1990-12-05 1991-01-23 Merck Sharp & Dohme Therapeutic agents
MX9200299A (en) 1991-02-07 1992-12-01 Roussel Uclaf NEW NITROGENATED BICYCLE DERIVATIVES, THEIR PROCEDURE FOR PREPARING THE NEW INTERMEDIATE COMPOUNDS OBTAINED THEIR APPLICATION AS MEDICINES AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.
GB9125515D0 (en) 1991-11-29 1992-01-29 Merck Sharp & Dohme Therapeutic agents
GB9125485D0 (en) 1991-11-29 1992-01-29 Merck Sharp & Dohme Therapeutic agents
ATE150751T1 (en) 1992-10-30 1997-04-15 Pfizer NEUROPROTECTION 3,4-DIHYDRO-2(1H)-QUINOLONES
FR2709489B1 (en) 1993-08-31 1995-10-20 Adir New derivatives of 2- (1H) -quinolineone, their preparation process and the pharmaceutical compositions containing them.
EP0933350A1 (en) 1994-12-30 1999-08-04 Ligand Pharmaceuticals Incorporated Tricyclic retinoids, methods for their production and use
GB9621757D0 (en) 1996-10-18 1996-12-11 Ciba Geigy Ag Phenyl-substituted bicyclic heterocyclyl derivatives and their use
AU7165798A (en) 1997-04-28 1998-11-24 Anticancer, Inc. Use of genistein and related compounds to treat certain sex hormone related conditions
IT1296985B1 (en) * 1997-12-19 1999-08-03 Zambon Spa BENZAZINIC DERIVATIVES INHIBITORS OF PHOSPHODIESTERASE 4
FR2784988B1 (en) * 1998-10-23 2002-09-20 Adir NOVEL DIHYDRO AND TETRAHYDROQUINOLEINIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP1147094A1 (en) 1999-01-15 2001-10-24 Novo Nordisk A/S Non-peptide glp-1 agonists
AU4128800A (en) 1999-04-16 2000-11-02 Astrazeneca Ab Estrogen receptor-beta ligands
US6413956B1 (en) 1999-05-06 2002-07-02 Neurogen Corporation Substituted 4-oxo-quinoline-3-carboxamides
FR2797444B1 (en) 1999-08-13 2003-02-07 Lafon Labor PHARMACEUTICAL COMPOSITIONS COMPRISING 4-QUINOLONES
AUPQ266199A0 (en) 1999-09-06 1999-09-30 Novogen Research Pty Ltd Compositions and therapeutic methods involving isoflavones and analogues thereof
TWI243173B (en) 1999-11-17 2005-11-11 Akzo Nobel Nv Spiro[2H-1-benzopyran-2,4'-piperidine] derivatives
FR2813791B1 (en) 2000-09-14 2004-03-12 Lafon Labor USE OF 2- AND 4-QUINOLONES TO INHIBIT INTIMAL NEO-PROLIFERATION
GB0023918D0 (en) 2000-09-29 2000-11-15 King S College London Antiparasitic compounds
US7226945B2 (en) 2000-10-13 2007-06-05 Astrazeneca Ab Estrogen receptor-β ligands
JP4256679B2 (en) 2001-03-16 2009-04-22 ノボゲン リサーチ ピーティーワイ リミテッド How to treat restenosis
AUPR846401A0 (en) 2001-10-25 2001-11-15 Novogen Research Pty Ltd 6-Hydroxy isoflavones, derivatives and medicaments involving same
SE0103648D0 (en) * 2001-11-01 2001-11-01 Astrazeneca Ab Therapeutic quinolone compounds
AU2002950217A0 (en) 2002-07-16 2002-09-12 Prana Biotechnology Limited 8- Hydroxy Quinoline Derivatives
US20050080024A1 (en) 2002-08-15 2005-04-14 Joseph Tucker Nitric oxide donating derivatives for the treatment of cardiovascular disorders
US20040033480A1 (en) 2002-08-15 2004-02-19 Wong Norman C.W. Use of resveratrol to regulate expression of apolipoprotein A1
GB0222516D0 (en) 2002-09-27 2002-11-06 Karobio Ab Novel compounds
CN1791408A (en) 2003-04-03 2006-06-21 普拉纳生物技术有限公司 Treatment of neurological conditions
EP1613322A4 (en) 2003-04-11 2008-08-13 Taigen Biotechnology Co Ltd Aminoquinoline compounds
US20060025337A1 (en) 2003-07-01 2006-02-02 President And Fellows Of Harvard College Sirtuin related therapeutics and diagnostics for neurodegenerative diseases
CA2541590A1 (en) 2003-10-10 2005-04-21 Resverlogix Corp. Treatment of diseases associated with the egr-1 enhancer element
EP1686981A4 (en) 2003-11-19 2011-02-23 Novogen Res Pty Ltd Combinational radiotherapy and chemotherapy compositions and methods
KR100636423B1 (en) 2004-04-30 2006-10-19 한국화학연구원 Novel quinolinone derivatives, a process for preparation thereof and pharmaceutical composition comprising the same
KR20070020036A (en) * 2004-05-18 2007-02-16 브라이트 퓨처 파마수티컬 라보라토리스 리미티드 Compositions for sleeping disorders
GB0420702D0 (en) * 2004-09-17 2004-10-20 Univ Birmingham Use of methanofullerene derivatives as resist materials and method for forming a resist layer
US8093273B2 (en) 2004-10-20 2012-01-10 Resverlogix Corp. Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases
EP1886996A1 (en) 2006-08-10 2008-02-13 Ferrer Internacional, S.A. 1H-Quinolin-4-one compounds, with affinity for the GABA receptor, processes, uses and compositions
TWI366565B (en) 2007-06-06 2012-06-21 Otsuka Pharma Co Ltd Quinolone compound and pharmaceutical composition
WO2009053799A1 (en) 2007-10-24 2009-04-30 Glenmark Pharmaceuticals, S.A. Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
CA2745015A1 (en) * 2008-12-05 2010-06-10 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical agent comprising quinolone compound
TWI472525B (en) * 2008-12-05 2015-02-11 Otsuka Pharma Co Ltd Quinolone compound and pharmaceutical composition

Also Published As

Publication number Publication date
CO6270258A2 (en) 2011-04-20
CY1111936T1 (en) 2015-11-04
SI2152699T1 (en) 2011-05-31
US9403773B2 (en) 2016-08-02
TWI366565B (en) 2012-06-21
NZ580919A (en) 2011-12-22
US20150218101A1 (en) 2015-08-06
AR066872A1 (en) 2009-09-16
KR20140021723A (en) 2014-02-20
ATE499368T1 (en) 2011-03-15
EP2152699A1 (en) 2010-02-17
KR20140097570A (en) 2014-08-06
TW200900382A (en) 2009-01-01
ES2360572T3 (en) 2011-06-07
CA2688448A1 (en) 2008-12-11
BRPI0812234A2 (en) 2014-12-16
RU2490259C2 (en) 2013-08-20
CN101679392A (en) 2010-03-24
US20160304461A1 (en) 2016-10-20
IL201894A (en) 2013-07-31
PT2152699E (en) 2011-04-04
KR101403817B1 (en) 2014-06-03
KR101536883B1 (en) 2015-07-14
WO2008150029A1 (en) 2008-12-11
UA98789C2 (en) 2012-06-25
HK1139153A1 (en) 2010-09-10
DK2152699T3 (en) 2011-04-18
CA2688448C (en) 2015-11-24
US20100130546A1 (en) 2010-05-27
IL201894A0 (en) 2010-06-16
EP2152699B1 (en) 2011-02-23
CN101679392B (en) 2012-05-30
KR20100028093A (en) 2010-03-11
HRP20110151T1 (en) 2011-05-31
MX2009013239A (en) 2010-01-25
AU2008260867A1 (en) 2008-12-11
RU2009149612A (en) 2011-07-20
DE602008005137D1 (en) 2011-04-07
KR101472262B1 (en) 2014-12-11
PL2152699T3 (en) 2011-07-29
JP2010528982A (en) 2010-08-26
US8269011B2 (en) 2012-09-18
KR20120012987A (en) 2012-02-13
US20140121207A1 (en) 2014-05-01
US8642619B2 (en) 2014-02-04
JP5063708B2 (en) 2012-10-31
KR101154613B1 (en) 2012-06-08
MY148098A (en) 2013-02-28
US20120316168A1 (en) 2012-12-13
US9045464B2 (en) 2015-06-02

Similar Documents

Publication Publication Date Title
US9403773B2 (en) Quinolone compound and pharmaceutical composition
US8592593B2 (en) Quinolone compound and pharmaceutical composition
JP5769504B2 (en) Medicine
EP2364706B1 (en) Pharmaceutical agent comprising quinolone compound
JP5247667B2 (en) Medicine

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
MK14 Patent ceased section 143(a) (annual fees not paid) or expired